unintentional weight loss

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unintentional weight loss

Andrew Olson, MD

CHIEF COMPLAINT

PATIENT

Mrs. M is an 85-year-old woman who comes to the office concerned about weight loss. She is worried that she has something serious.

What is the differential diagnosis of unintentional weight loss? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

Significant unintentional weight loss is defined as > 5% loss of usual body weight in the last 6–12 months and can be a harbinger of serious underlying disease. One study documented significantly increased mortality in men with unintentional weight loss compared with men whose weight was stable or increased (36% vs ≈ 15%). The evaluation of unintentional weight loss is complicated by its frequency among older adults; 15–20% of adults over 65 years of age may have unintentional weight loss, and the prevalence rises to 50–60% among nursing home residents. Body weight usually peaks about age 60 and then decreases gradually thereafter, especially after age 70, although the normal changes are small (< 1 lb/year).

It should be noted that weight loss in the elderly is often part of an overall syndrome of functional decline called frailty, which includes weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss. When present, frailty has significant implications for morbidity and mortality in the elderly and frail patients have substantially higher morbidity and mortality that their age-matched peers.

There are a large number of diseases that can cause unintentional weight loss, which are best organized by system (see below). The most common causes of unintentional weight loss in published studies are cancer (most commonly gastrointestinal [GI] but also lung, lymphoma, and other malignancies), ≈ 19–36%; depression and alcoholism, 16%; nonmalignant GI diseases, 13%; and unknown, 22%. Endocrine disorders account for 7% of unintentional weight loss. Although cancer is the most common cause, it is not the cause in most patients. Mild cognitive impairment and dementia may also cause weight loss due to a combination of increased energy expenditure (due to agitation and pacing) and decreased caloric intake.

Four pivotal points are worth remembering when evaluating patients with unintentional weight loss (Figure 32-1). First, the weight loss should be documented if possible; 25–50% of patients that complain of unintentional weight loss have not in fact lost weight (and do not need to be evaluated for causes of weight loss). Elderly adults often lose muscle mass and simply look like they lost weight. Weight loss should be documented by comparing prior weights or, if these are unavailable, by finding a significant decrease in a patient’s clothing and/or belt size. It may also be helpful to see corroborating information from family and/or caretakers and trying to elicit a specific amount of weight loss from the patient.

Clinicians should verify the weight loss or document significant changes in the patient’s clothing or belt size.

The second pivotal step identifies patients with malabsorption. Patients should be asked about changes in their bowel movements, including diarrhea or large, difficult to flush or malodorous stools. Although an uncommon cause of unintentional weight loss, such symptoms suggest small bowel or pancreatic disease and direct the diagnostic search. Additionally, difficulty with defecation or changes in stool caliber raises the possibility of colorectal cancer.

The third pivotal step differentiates weight loss that is due to decreased caloric intake from weight loss that is due to increased caloric expenditure or malabsorption. Most patients lose weight due to decreased caloric intake. Weight loss associated with normal or increased intake suggests substantial catabolism or energy loss that may be seen in patients with cancer, severe chronic obstructive pulmonary disease, hyperthyroidism, malabsorption, or poorly controlled diabetes.

Fourth and most importantly: a clinician is most likely to be successful in identifying the cause of a patient’s unintentional weight loss if she identifies the “company it keeps.” Clinicians should perform a truly comprehensive history (including a review of systems, psychosocial history, and medication history) and perform a detailed head to toe physical exam (with special attention to the mental status exam) to identify any abnormalities. An initial baseline laboratory evaluation should include a complete blood count (CBC) with differential, urinalysis, renal panel, calcium, hepatic panel, fasting glucose, fecal occult blood test (FOBT), erythrocyte sedimentation rate (ESR), thyroid-stimulating hormone (TSH), HIV test, and chest radiograph. Abnormal, or potentially abnormal, findings discovered on history, physical exam, or initial labs are rarely conclusively diagnostic but often provide critical clues to the underlying diagnosis and should be thoroughly evaluated. Examples of such findings include anemia, which may be due to iron deficiency from an unsuspected carcinoma of the colon or stomach; an elevated alkaline phosphatase, which may be due to metastatic disease to the liver or bones; hematuria, which may be due to carcinoma of the kidney or bladder; or a markedly elevated ESR, which may be due to multiple myeloma, temporal arteritis, subacute bacterial endocarditis (SBE), or other chronic infection. Additionally, recommended preventive health exams should be brought up to date (eg, mammogram, Papanicolaou exam with human papillomavirus testing, colonoscopy or other appropriate colorectal cancer screening, prostate-specific antigen in selected patients and low-dose chest CT scan for smokers with ≥ 30 pack year smoking history unless they quit > 15 years previously).

Patients without any such clues may benefit from an upper endoscopy and an abdominal ultrasound. Figure 32-1 illustrates the diagnostic approach.

Figure 32-1. Diagnostic approach: unintentional weight loss.

Interestingly, an unrevealing initial evaluation is reassuring: one study conducted in patients with weight loss showed that among those who underwent evaluation, none of those without abnormal or concerning findings on the initial evaluation were diagnosed with cancer during the study. A more recent, larger study showed that cancer may be undiagnosed antemortem but discovered on autopsy; this suggests that, while the rate of cancers diagnosed on follow-up (after the initial evaluation) is low, cancers may still be present and thus warrant ongoing clinical follow-up.

Differential Diagnosis of Involuntary Weight Loss

The differential diagnosis of weight loss is extensive and best organized by system.

A.  Cardiovascular

1.  Heart failure (severe)

2.  SBE

B.  Endocrine

1.  Adrenal insufficiency

2.  Diabetes mellitus

3.  Hyperthyroidism

C.  GI (organized from mouth to rectum)

1.  Poor dentition (50% of patients edentulous by age 65, oral problems account for up to 9% of unintentional weight loss in adults > 65 years)

2.  Anosmia with decreased pleasure from food, altered gustation from another cause

3.  Esophageal disorders

a.  Esophageal stricture or web

b.  Dysmotility

c.  Esophageal cancer

4.  Gastric disorders

a.  Peptic ulcer disease (PUD)

b.  Gastric cancer

c.  Gastroparesis

d.  Gastric outlet obstruction

5.  Small bowel diseases

a.  Mesenteric ischemia (chronic)

b.  Crohn disease

c.  Celiac disease

d.  Bacterial overgrowth syndromes

e.  Lactose intolerance

6.  Pancreatic disease

a.  Acute pancreatitis (or its complications)

b.  Chronic pancreatitis

c.  Pancreatic insufficiency

d.  Pancreatic cancer

7.  Hepatic disease

a.  Hepatitis (viral, alcoholic, nonalcoholic steatohepatitis, others)

b.  Cirrhosis

c.  Hepatocellular carcinoma

8.  Biliary disease: symptomatic cholelithiasis (with food avoidance)

9.  Colonic diseases

a.  Chronic constipation (either primary or secondary to medications or another process)

b.  Colorectal cancer

c.  Ischemic colitis

10.  Chronic GI infections (more likely in immunocompromised persons)

a.  Giardia lamblia

b.  Clostridium difficile

c.  Entamoeba histolytica

d.  Viral enteritis with prolonged carriage (especially in immunocompromised persons)

D.  Hematologic/oncologic

1.  Lung cancer

2.  Pancreatic cancer

3.  GI cancers

4.  Lymphoma

5.  Miscellaneous others

E.  Infectious: HIV infection or complications

F.  Neurologic

1.  Dementia or cognitive impairment

2.  Stroke

3.  Parkinson disease or parkinsonism

G.  Psychiatric

1.  Depression

2.  Anxiety

3.  Bipolar

4.  Schizophrenia

H.  Psychosocial

1.  Poverty with food insecurity (15% of patients over age 65 live below the poverty line)

2.  Isolation

3.  Immobility or inadequate transportation

I.  Substance abuse/dependence:

1.  Alcohol use disorder

2.  Opioid use disorder

3.  Other substance use disorder (methamphetamine, others).

J.  Renal/metabolic

1.  Uremia

2.  Hypercalcemia

K.  Respiratory

1.  Chronic obstructive pulmonary disease (severe)

2.  Bronchiectasis

3.  Tuberculosis

4.  Lung cancer

L.  Rheumatologic

1.  Polymyalgia rheumatica

2.  Temporal arteritis

3.  Rheumatoid arthritis

4.  Systemic lupus erythematosus

5.  Sjögren syndrome

M.  Miscellaneous

1.  Drugs (eg, digoxin, loop diuretics, diltiazem, levodopa, metformin, opioids, certain selective serotonin reuptake inhibitors [SSRIs], and many others)

2.  Medical diets

3.  Radiation

4.  Chronic pain

5.  Frailty syndrome

Mrs. M reports that she has lost weight over the last 6 months and notes that her appetite is not as good as previously. She does not weigh herself and is unsure of how many pounds she has lost.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

The patient’s relatively nonspecific history is typical of many patients complaining of weight loss. Patients report an unspecified amount of weight loss that is associated with anorexia. The first pivotal step in the evaluation is to verify that weight loss has, in fact, occurred.

Mrs. M is new to the clinic and prior weights are unavailable. While Mrs. M does not know how many pounds she has lost, she does report that her clothes are much too loose and she has needed to buy pants that are 2 sizes smaller.

Mrs. M’s change in clothing size suggests true and significant weight loss. The second pivotal step in evaluating patients with documented weight loss determines whether the patient has symptoms suggestive of malabsorption, such as diarrhea or floating stools.

Mrs. M does reports that she has a bowel movement daily or every other day. She notes no diarrhea, no floating or difficult to flush stools, and no change in her bowel habits over the last several years.

Since the history does not suggest diarrhea or malabsorption, the third pivotal step in the evaluation of patients with unintentional weight loss differentiates weight loss due to decreased caloric intake or absorption from that due to increased caloric expenditure. Mrs. M.’s initial complaint already clarified that her weight loss was due to anorexia and decreased caloric intake. The fourth step is a comprehensive, system-based approach utilizing a thorough history, (including a past medical history, detailed psychosocial history, and review of systems), physical exam, basic laboratory tests, and completion of her age-appropriate health maintenance examinations to search for diagnostic clues.

Mrs. M’s past medical history is unrevealing, including a review in the Electronic Health Record. Her psychosocial history is also unrevealing. She lives with her husband (who is in good health), and they have no difficulty obtaining or cooking food. She has never smoked tobacco and drinks alcohol rarely. The review of systems is negative in detail.

On physical exam, Mrs. M looks cachectic and fatigued. Her vital signs are normal. HEENT exam reveals no oral lesions or adenopathy. Lungs are clear to percussion and auscultation. Cardiac exam reveals a normal rate and regular rhythm, with a grade II flow systolic murmur along the left sternal border without radiation. Her abdomen is scaphoid, without hepatosplenomegaly or mass. FOBT is negative. Neurologic exam is normal, including a Mini- Mental State Exam on which her score is 29/30.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Unfortunately, like many patients with unintentional weight loss, Mrs. M has no specific clues to suggest any particular diagnosis. Given her cachectic appearance (suggesting her weight loss is real despite the lack of documentation) and the fact that cancer is the most common cause of unintentional weight loss and a must not miss hypothesis, it is the leading hypothesis that must be evaluated at this point. Her tired appearance also raises the possibility of depression (which could be either a primary psychiatric disorder or a reaction to an underlying medical condition). Finally, nonmalignant GI disease should also be considered, since it is also a common cause of unintentional weight loss. Hyperthyroidism is also on the differential. Table 32-1 lists her differential diagnosis.

Table 32-1. Diagnostic hypotheses for Mrs. M.

Leading Hypothesis: Cancer Cachexia

Textbook Presentation

Patients with cancer cachexia often have advanced disease. Weight loss in cancer may be due to decreased caloric intake (anorexia), increased caloric expenditure, or both. They may have other symptoms specific to their particular malignancy. The cancer may have been diagnosed before the weight loss or the weight loss may lead to the diagnosis.

Disease Highlights

A.  Cancer diagnoses account for up to 36% of cases of unexplained weight loss.

B.  The most common malignancies associated with weight loss are GI, lung, and lymphoma.

C.  Weight loss is one of the most common presenting symptoms in patients with lung cancer (comparable to cough). It is more frequent than dyspnea, hemoptysis, or chest pain.

D.  Unintentional weight loss is common in cancer patients. At the time of diagnosis, 24% of patients with cancer have lost weight.

E.  Weight loss increases the risk of immobility, deconditioning, and adversely affects immunity. The risk of pulmonary embolism, pressure injuries (formerly pressure ulcers), and pneumonia are increased.

Evidence-Based Diagnosis

A.  Patient estimation of weight loss compared to actual measurement

1.  In patients who overestimated their weight loss (by more than 0.5 kg), cancer was unlikely (6%) and no organic cause was found in 73%.

2.  In patients who underestimated their weight loss (by more than 1 kg), cancer was diagnosed in 52%.

B.  Several studies have evaluated the history, physical exam, and initial laboratory studies to aid in the detection of cancer in patients with unintentional weight loss.

C.  Laboratory studies usually included a CBC, chemical survey (including glucose, calcium, blood urea nitrogen [BUN], creatinine, and liver biochemical tests), HIV when appropriate, ESR, TSH, C-reactive protein (CRP), urinalysis, and chest radiograph. Several of these studies also incorporated abdominal ultrasound.

D.  Further work-up was dictated by abnormalities detected in the initial evaluation. (For instance, GI evaluation with upper endoscopy and colonoscopy would be initiated in patients with GI complaints or iron deficiency anemia; hepatobiliary and pancreatic imaging would be done in those with abdominal pain or abnormal liver biochemical tests, etc.)

1.  Cancer was detected in 14–28% of patients in these studies.

2.  The battery was 93% sensitive for the detection of cancer in patients with unintentional weight loss.

3.  The rate of occult cancer in patients for whom an initial evaluation was unrevealing is low (< 5%).

Cancer is an unlikely cause of weight loss in patients with a negative initial evaluation (including appropriate follow-up of abnormalities).

Treatment

A.  Nutritional support

1.  In many patients, artificial nutritional support is not effective.

2.  Certain subgroups of patients may benefit from nutritional support; these are generally patients with a reversible mechanical cause leading to inadequate oral intake.

a.  Head and neck cancer (after radiation therapy)

b.  Bowel obstruction

c.  Surgery patients (particularly upper GI tract cancer)

d.  Patients receiving high-dose chemotherapy

3.  Enteral support is strongly favored when possible over parenteral nutrition.

B.  Treat underlying malignancy

C.  Medroxyprogesterone and megestrol

1.  Decreases nausea and anorexia and increases weight gain

2.  May increase the risk of thromboembolic events

3.  Other side effects include hyperglycemia, endometrial bleeding, edema, hypertension, and adrenal suppression and insufficiency

D.  Corticosteroids

1.  Decrease anorexia and nausea

2.  Increase appetite, quality of life, and feeling of well-being

3.  Because of the side effects, corticosteroids are often reserved for patients with terminal disease.

E.  A variety of other medications have been tried with limited to no success.

1.  Prokinetic drugs (metoclopramide) can decrease anorexia and nausea but did not increase appetite or caloric intake.

2.  The cannabinoid dronabinol was less effective than progestins.

3.  Other agents under study include gherlin, melatonin, ATP infusions, and oxandrolone.

4.  Studies about the use of cannabis are lacking despite increasing availability for medical use.

MAKING A DIAGNOSIS

Clearly, a diagnosis is not yet apparent on history or physical exam for Mrs. M. The data suggest that when the cause of unintentional weight loss is malignant, there are usually clues on history, physical exam, or on laboratory testing. You elect to check a CBC, liver panel, renal panel, urinalysis, chest radiograph, and screening mammogram. Finally, you elect to schedule Mrs. M for a colonoscopy, since she has never undergone colon cancer screening. You discuss that this is different than usual age-appropriate colon cancer screening, for which she is above the age at which screening is still recommended; this is a diagnostic evaluation with a substantially different pretest probability.

Surprisingly, Mrs. M’s laboratory evaluation is normal. Her CBC is normal without evidence of iron deficiency anemia (which could have suggested gastric or colorectal cancer). The chest radiograph is also normal, making lung cancer unlikely, particularly in a patient who never smoked. ALT, AST, alkaline phosphatase, and bilirubin were normal and her kidney function is normal. Her HIV test is negative and there was no hematuria on urinalysis (which could suggest renal cell carcinoma or bladder cancer). Her mammogram and colonoscopy were normal.

Have you crossed a diagnostic threshold for the leading hypothesis, cancer cachexia? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: Depression

Textbook Presentation

Depression may follow a recognizable loss or occur without a clear precipitant. Classically, patients complain of profound sadness, lack of interest in activities (anhedonia), sleep and appetite disturbances, impaired concentration, and other symptoms. Patients may lose or gain weight. Patients may experience suicidal or homicidal thoughts.

Disease Highlights

A.  Point prevalence of major depressive disorder (MDD) is 5–13%. Lifetime prevalence of MDD is 16.2%, and minor depression is twice as common.

B.  Depression is the second most common condition seen in primary care practices and the fourth leading cause of disability.

C.  Recurrences are common, up to 50% in 1 year, and many patients require lifelong therapy.

D.  Risk factors for major depression

1.  Prior episode of depression

2.  Postpartum period

3.  Comorbid medical illness

4.  Older age

5.  Concomitant neurologic disease

6.  Chronic pain

7.  Absence of social support

8.  Female sex (2–3 times more common than in males)

9.  Family history (first-degree relative)

10.  Stressful life events (must be differentiated from adjustment disorder)

11.  Substance abuse/dependence

12.  Unemployment and low socioeconomic status

E.  Associated anxiety: 50% of patients with depression have anxiety symptoms

1.  10–20% of patients with MDD have evidence of panic disorder and 30–40% have evidence of generalized anxiety disorder.

2.  Patients with anxiety and MDD are at higher risk for suicide.

F.  Minor depression

1.  10–18% progress to major depression within 1 year.

2.  20% have moderate to severe disability.

Evidence-Based Diagnosis

A.  The DSM-5 criteria for MDD require 5 of the following 9 criteria (1 of which is depressed mood or anhedonia) for at least 2 weeks:

1.  Depressed mood most of the day, nearly every day

2.  Anhedonia with “marked diminished interest or pleasure in all or almost all activities”

3.  Significant appetite or weight change (> 5% of body weight in 1 month not associated with dieting)

4.  Sleep disturbance (insomnia or hypersomnia)

5.  Psychomotor agitation or retardation

6.  Fatigue

7.  Feelings of worthlessness or excessive or inappropriate guilt

8.  Impaired concentration

9.  Suicidal ideation

B.  These criteria must be associated with significant distress or impaired functioning and not be secondary to substance abuse or another medical condition; in addition, there should be no prior history of mania (which would be diagnostic of a bipolar disorder).

C.  Minor depression requires 2–4 of the above symptoms, including anhedonia or depressed mood for > 2 weeks.

D.  There are multiple validated screening tools for depression, including the 2-item Patient Health Questionnaire (PHQ-2), the 9-item Patient Health Questionnaire (PHQ-9) and the Geriatric Depression Scale.

E.  Severity can be estimated using the Hamilton Rating Depression Scale. Scores of ≤ 18 are classified as mild to moderate, 19–22 as severe, and ≥ 23 as very severe depression.

F.  The sadness that accompanies major loss (grief), as in bereavement, may be difficult to distinguish from MDD and the 2 may coexist. Profound sadness, anorexia, insomnia, and weight loss may occur. Features that suggest grief (rather than MDD) include:

1.  The ability to have periods of happiness or pleasure in grief that is often absent in MDD.

2.  Sadness in grief is often episodic rather than pervasive and constant.

3.  In grief, the focus of sadness is typically on loss rather than self-loathing or worthlessness seen in MDD.

G.  Screening

1.  Depression is often missed on routine evaluation. In patients in whom depression was subsequently diagnosed, only 8.8% were found to be depressed during the routine interview.

2.  Screening tools increase the identification of patients with depression by 2- to 3-fold (an absolute increase of 10– 47%). Again, specific validated screening tools allow for standardization, and are easily used in primary care workflows. Furthermore, screening coupled with treatment decreases clinical morbidity.

Depression is frequently missed in unstructured clinical encounters. Screening tools are invaluable aids to its diagnosis.

3.  Screening is recommended by the US Preventive Services Task Force (USPSTF).

4.  2 screening questions perform as well as more complex tools (a positive response to either question is considered positive).

a.  “Over the past 2 weeks, have you felt down, depressed, or hopeless?”

b.  “Over the past 2 weeks, have you felt little interest or pleasure in doing things?”

c.  Sensitivity, 96–97%; specificity, 57–67%; LR+, 2.2–2.9; LR−, 0.04–0.07

d.  Patients with a positive response to either question should undergo a full diagnostic evaluation to determine if they meet diagnostic criteria for depression and to exclude a history of mania.

5.  Clinical clues that might suggest a patient is depressed include

a.  Recent stress or loss

b.  Chronic medical illness, chronic pain syndromes

c.  > 6 physical symptoms

d.  Higher patient ratings of symptom severity

e.  Lower patient rating of overall health

f.  Physician perception of encounter as difficult

g.  Substance abuse (23% have MDD)

h.  Functional restriction is greater than explained by their medical illness.

i.  The language used to describe their condition is extreme (terrible, unbearable, etc).

j.  Sleep disturbances

6.  Many medical illnesses cause weight loss and depression (eg, 20–45% of patients with cancer are depressed, and 40% of patients with Parkinson disease are depressed). Even in patients with depression, care must be taken before ascribing weight loss solely to depression.

The diagnosis of depression does not exclude other serious illnesses causing unintentional weight loss. Patients should be monitored to ensure weight gain or stabilization following treatment of their depression.

The evaluation of a depressed patient with weight loss should include a complete physical examination and review of systems to avoid premature closure.

Treatment

A.  Work-up should include a full psychosocial history, including degree of functional impairment, history of domestic violence, and a drug history to look for agents that can worsen or precipitate depression (opioids, alcohol, interferon, L-dopa, corticosteroids, oral contraceptives, propranolol, cocaine).

B.  Patients should be screened for a history of manic symptoms that suggest bipolar illness (periods of reduced need for sleep, impulsivity, euphoric mood, racing thoughts, increased sexual activity, and grandiosity).

C.  Screening tests (ie, TSH, basic metabolic panel, liver biochemical tests, CBC) are recommended to rule out medical conditions (eg, hypothyroidism) that can simulate or cause depression.

D.  Assess suicide risk: Ideation, intent, or plan

1.  Have you been having thoughts of dying?

2.  Do you have a plan?

3.  Does patient have the means (eg, weapons) to carry out their plan?

4.  Risk factors include

a.  Older men

b.  Psychotic symptoms

c.  Alcohol or other substance abuse

d.  History of prior attempts

e.  Family history of suicide or recent exposure to suicide

5.  Risk factors for suicide attempts in black patients included young age (OR 9.4), less than high school education (OR 3.6), mood disorder (OR 3.8), anxiety disorder (OR 6.0), and substance abuse (OR 4.5).

6.  Emergent psychiatric evaluation should be performed in suicidal patients who have risk factors, who appear intoxicated, cannot contract for safety, or have poor social support.

E.  Pharmacotherapy

1.  Based on the number of symptoms and functional impairment

2.  Not influenced by whether or not there is well-defined precipitant (ie, stress). Therapy should be strongly considered in grieving patients with persistent symptoms of MDD for more than 2 months after a loss.

3.  Multiple classes of medications are effective: SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

4.  A patient-level meta-analysis reported that pharmacotherapy was effective. The benefit is most marked in patients with very severe depression (Hamilton Depression Rating Scale ≥ 25). The numbers needed to treat are 16, 11, and 4 for patients with mild to moderate, severe, and very severe depression, respectively.

5.  SSRIs are often used as first-line agents due to low frequency of adverse effects and safety in overdose. Both SSRIs and SNRIs may cause sexual dysfunction. Venlafaxine (an SNRI) can be lethal in overdose.

6.  Caution is recommended in the use of SSRIs in certain age groups:

a.  The USPSTF concluded that fair evidence suggests that SSRIs increase suicidal behaviors in patients 18–29 years of age, especially those with MDD who receive paroxetine (OR 6.7; CI, 1.1–149.4). The risk was highest in the first month of treatment.

b.  For those age groups, alternative medications or psychotherapy may be preferred.

7.  Mirtazapine may be useful in patients with weight loss, poor appetite, and insomnia and bupropion may be useful in patients with daytime lethargy and fatigue.

8.  TCAs frequently cause troubling anticholinergic side effects (including dysrhythmias), significant weight gain (> 20 lbs) and are dangerous in overdose, so they are used less frequently. High-dose TCAs may increase the risk of sudden cardiac death.

9.  MAOIs interact with a variety of tyramine-containing foods and medications and may precipitate a hypertensive crisis. Typically, only psychiatrists prescribe these.

10.  Patients with a prior history of manic symptoms should be referred for psychiatric evaluation prior to the institution of antidepressant therapy. Antidepressant therapy can trigger mania.

11.  Continue treatment for 6–9 months after clinical recovery.

12.  Patients with multiple recurrences (≥ 2–3) may require lifetime therapy.

F.  Psychotherapy

1.  Equally effective as pharmacotherapy in patients with mild to moderate depression. Options include cognitive behavioral therapy, problem-solving therapy, and interpersonal psychotherapy.

2.  Less effective than pharmacotherapy in patients with severe depression. Combined psychotherapy and pharmacotherapy may be the best option.

G.  Exercise programs may be helpful in older adults with mild to moderate depression.

H.  Electroconvulsive therapy is an alternative therapy for patients with severe, refractory depression, particularly those with psychotic or suicidal features.

I.  Indications for referral include psychotic features; substance abuse; panic disorder; agitated, severe, or relapsing depression; bipolar features; suicidality; and dysthymia.

Mrs. M reports no unusual stresses or losses. She lives with her husband, regularly sees her daughter and other family members, and remains actively involved in her church. She denies feeling down, depressed or hopeless in the last month and denies loss of interest or pleasure in doing things. Her score on the PHQ-2 instrument is 0.

Mrs. M’s answers to the screening questions make depression highly unlikely (LR− 0.07). Although her appearance seems antithetical to what you know about hyperthyroidism, you wonder if that possibility should be pursued.

Alternative Diagnosis: Hyperthyroidism

Textbook Presentation

Classical symptoms include palpitations, heat intolerance, increased sweating, insomnia, tremulousness, diarrhea, and weight loss. Signs of hyperthyroidism include sinus tachycardia, systolic hypertension, frightened stare, an enlarged goiter, a fine resting tremor, and exophthalmos (only if hyperthyroidism is secondary to Graves disease). Other manifestations may include hyperpigmentation, irregular menses, pruritus, and thinning of hair. Complications that occur over time include osteoporosis, tracheal obstruction or dysphagia (from the goiter), tachyarrhythmias (particularly atrial fibrillation), high output heart failure, anemia, and proximal muscle weakness.

Disease Highlights

A.  Prevalence, 0.3%.

B.  Hyperthyroidism is actually an endocrine syndrome caused by several distinct pathophysiologic entities (Table 32-2).

Table 32-2. Distinguishing features of several hyperthyroid states.

Evidence-Based Diagnosis

A.  History and physical exam

1.  Certain findings of hyperthyroidism are quite specific (ie, lid lag and lid retraction) and help rule in the diagnosis (specificity, 99%; LR+, 17−32).

2.  However, clinical findings are not highly sensitive. Therefore, absent clinical findings do not rule out hyperthyroidism.

a.  Goiter is present in 70–93% of cases.

b.  Pulse > 90 bpm is present in 80% of cases.

c.  Lid lag is present in 19% of cases.

d.  Ophthalmopathy is present in 25–50% of patients with Graves disease.

e.  Hyperreflexia is variable depending on the age of the patient.

B.  Elderly patients

1.  Prevalence of hyperthyroidism in the elderly is 2–3%.

2.  Hyperthyroidism often presents atypically in elderly patients. Expected adrenergic findings are often absent, whereas atrial fibrillation is more common, resulting in the phenomenon referred to as apathetic hyperthyroidism of the elderly. Table 32-3 compares the findings in young and older patients with hyperthyroidism.

Table 32-3. Sensitivity of findings in patients with hyperthyroidism.

Consider hyperthyroidism in elderly patients with weight loss (OR 8.7), tachycardia (OR 11.2), atrial fibrillation, or apathy (OR 14.8). Hyperthyroidism was not even considered initially in 54% of admitted patients in whom hyperthyroidism was subsequently diagnosed.

C.  Laboratory tests

1.  TSH is the test of choice for hyperthyroidism (in the absence of pituitary disease) (sensitivity > 99%, specificity > 99%, LR+, > 99, LR−, <.01).

a.  Low TSH usually indicates hyperthyroidism.

b.  Normal TSH usually indicates euthyroidism.

c.  High TSH usually indicates hypothyroidism.

2.  Exceptions to the above occur when the pituitary itself is diseased (rare).

a.  Pituitary adenomas can produce TSH, causing hyperthyroidism with increased TSH and free T4.

b.  Pituitary dysfunction or destruction (eg, from sarcoidosis or tumors) results in hypothyroidism with decreased TSH and free T4.

3.  T4 measurements

a.  The total T4 measures the total thyroid hormone in the serum, including both the free T4 and T4 bound to thyroid-binding globulin (TBG).

b.  Free T4 is active and more accurately reflects thyroid activity than the total T4 (which is affected by the level of TBG). The free T4 should be ordered when the TSH is abnormal.

c.  Caution should be taken when evaluating thyroid hormone levels in acutely ill patients.

4.  Occasionally, patients with hyperthyroidism have isolated elevations in T3, (referred to as T3 thyrotoxicosis). In such patients, the TSH is still suppressed.

5.  An approach to thyroid function tests is shown in Figure 32-2.

Figure 32-2. Diagnosis of thyroid function disorders. (Reproduced with permission from Muller AF, Berghout A, Wiersinga WM, et al: Thyroid function disorders–Guidelines of the Netherlands Association of Internal Medicine, Neth J Med. 2008 Mar;66(3):134–142.)

6.  Established hyperthyroidism

a.  Certain features can help distinguish the etiology of hyperthyroidism, including thyroid-stimulating immunoglobulin and radioactive iodine uptake scan (see Table 32-2). The two most common causes are Graves disease and toxic multinodular goiter.

b.  Doppler flow can be useful in patients unable to undergo the radioactive uptake scan (eg, pregnant women). Increased flow correlates with increased uptake.

c.  Premenopausal women should have a pregnancy test performed prior to iodine scanning or instituting therapy.

d.  Imaging with ultrasound or occasionally CT scan or MRI can be useful in patients with large goiters, particularly if there is a suggestion of airway obstruction.

Treatment

A.  Beta-blockers can be used primarily to decrease the symptoms arising from the sympathetic stimulation including the tremor, tachycardia, palpitations, and sweating.

B.  Definitive treatment of hyperthyroidism depends on underlying etiology.

1.  Graves disease or toxic multinodular goiter: Options include antithyroid drugs, radioactive iodine or surgery.

a.  Antithyroid drugs (methimazole, carbimazole and propylthiouracil)

(1)  Act rapidly

(2)  Rarely cause agranulocytosis (0.1–0.3%)

(3)  ≈ 40% of patients relapse

(4)  Require frequent monitoring

(5)  Methimazole is preferred over propylthiouracil due to its more rapid onset of action and lower incidence of hepatotoxicity. However, propylthiouracil is preferred for women in their first trimester of pregnancy or patients in thyroid storm.

b.  Radioactive iodine

(1)  Used successfully for over 60 years.

(2)  ≈ 21% relapse rate

(3)  Pretreatment with antithyroid drugs is advised for some patients.

(4)  Contraindications include pregnancy, lactation, and severe ophthalmopathy.

(5)  Results in permanent hypothyroidism and the requirement for lifelong thyroid hormone replacement.

c.  Surgery

(1)  Occasionally used, particularly if the goiter is troublesome.

(2)  Pretreatment with antithyroid drugs is advised for some patients.

(3)  Results in permanent hypothyroidism and the requirement for lifelong thyroid hormone replacement.

(4)  Complications may include hypoparathyroidism, recurrent laryngeal nerve damage, and postoperative thyroid storm.

2.  Subacute thyroiditis

a.  Aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) decrease thyroid inflammation. Prednisone can be used in severe cases.

b.  Hyperthyroidism is usually transient and does not require antithyroid drugs. Beta-blockers are used to decrease symptoms of hyperthyroidism until the inflammation subsides.

c.  Transient mild hypothyroidism may develop as the thyroiditis resolves. Occasionally, treatment with levothyroxine is required.

CASE RESOLUTION

Mrs. M’s TSH is completely suppressed (< 0.1 microunits/mL). The T4 is elevated at 20 mcg/dL (nl 5–11.6 mcg/dl) and the free T4 is 3.6 (nl 0.0–1.8 ng/L). You diagnose primary hyperthyroidism. A thyroid scan reveals heterogeneous uptake consistent with a toxic multinodular goiter.

Check the TSH on every patient evaluated for weight loss.

Due to her advanced age, you elect to have her treated with radioactive iodine. Six months later she returns; she is taking replacement levothyroxine for the radioactive iodine–induced hypothyroidism. Laboratory exam reveals that she is euthyroid and she feels well. She has gained 10 pounds.

CHIEF COMPLAINT

PATIENT

Mr. O is a 55-year-old man who complains of weight loss. He reports that he has tried for years to lose weight (unsuccessfully) but that recently he has lost more and more weight without effort. He was initially pleased but recently has become concerned. He reports that he has lost 30 pounds in the last 6 months (from 200 lbs to 170 lbs).

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

As noted above, the first pivotal step in the evaluation of unintentional weight loss is to verify the weight loss. Mr. O has clearly suffered from verifiable significant unintentional weight loss. The second pivotal step in the evaluation of patients with documented weight loss is to determine whether or not the patient is having symptoms that suggest malabsorption.

Mr. O reports no diarrhea, large foul-smelling stools, or difficult to flush stools. He reports that he previously moved his bowels once a day but lately only once every other day. He attributes this to his decreased appetite and decreased oral intake.

Since Mr. O’s weight loss is not obviously secondary to malabsorption, the focus turns to the third pivotal step, which differentiates weight loss due to decreased caloric intake or absorption from that due to increased caloric expenditure. Like many patients with weight loss Mr. O clearly notes a decreased oral intake and the evaluation focuses on the fourth pivotal step; a comprehensive, system-based approach utilizing a thorough history, (including a past medical history, detailed psychosocial history, and review of systems), physical exam, basic laboratory tests and completion of age-appropriate health maintenance examinations to search for diagnostic clues that will guide further evaluation.

Mr. O notes that he has a decreased appetite and feels full quickly after starting to eat. His past medical history is unremarkable as he has been well except for mild osteoarthritis of the knee. On psychosocial history, he reports that he has not felt down, depressed, or hopeless during the past month nor has he been bothered by a lack of interest in activities. He denies any changes at home and has no trouble obtaining food. He has never used tobacco and drinks 2 beers about once a month.

On review of systems, there are no fevers, night sweats, swollen lymph nodes, muscle aches, headaches, shortness of breath, cough, heat intolerance, palpitations or tremulousness. There are also no GI symptoms of oral pain, dysphagia, odynophagia, melena, hematochezia, abdominal pain, or jaundice.

His medications include 600 mg of ibuprofen 2–3 times a day for mild osteoarthritis of his left knee. Physical exam reveals a thin but otherwise healthy appearing middle-aged man. Vital signs are normal. The remainder of his exam is completely normal.

Laboratory tests, including CBC with differential, hepatic panel, renal panel, urinalysis, CRP, ESR, and TSH, are normal. HIV and FOBT are negative. A chest radiograph is normal without mass or adenopathy.

The cause of Mr. O’s weight loss is not immediately obvious. However, his early satiety and NSAID use are clues that suggest peptic ulcer disease (PUD), gastritis, or gastric cancer. You consider PUD your leading hypothesis. Gastric cancer is an alternative hypothesis, and colon cancer is a must not miss hypothesis given his change in bowel habits. Table 32-4 lists the differential diagnosis.

Table 32-4. Diagnostic hypotheses for Mr. O.

All medications (prescription, over-the-counter and traditional/herbal) should be carefully scrutinized in patients complaining of unintentional weight loss. Some medications cause anorexia directly by suppressing appetite, while others act through various organ toxicities.

Colon cancer causing subtotal obstruction may present as a change in bowel habits, either constipation or diarrhea.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: PUD

Textbook Presentation

The pain of PUD is classically described as a dull or hunger-like pain in the epigastrium that is either exacerbated or improved by food intake. The pain is often worse on waking and may radiate to the back. Symptomatic periods often last for several weeks. Nausea and early satiety may be seen.

Disease Highlights

A.  250,000 cases per year in the United States

B.  Etiology: In the United States, most ulcers are secondary to NSAID use, Helicobacter pylori infection or both. The prevalence of H pylori varies widely depending on the region.

1.  H pylori infection

a.  Present in 50% of the world’s population

b.  Asymptomatic in the majority of patients

c.  Peptic ulcers (in the stomach or duodenum) develop in 1–10% of infected patients.

d.  H pylori may also cause atrophic gastritis, intestinal metaplasia, and rarely, gastric cancer (0.1–3% of infected patients).

2.  NSAIDs

a.  Virtually all NSAIDs increase the risk of PUD, including over-the-counter NSAIDs and low-dose aspirin. The risk is lower with cyclooxygenase (COX)-2 inhibitors.

b.  Ulcer disease develops in 25% of persons who take NSAIDs regularly.

c.  PUD-related bleeding or perforation is present in 2–4% of persons who take NSAIDs regularly.

d.  Results in 100,000 NSAID-associated hospitalizations in the United States annually, with 7000–10,000 deaths.

e.  Gastric ulcers are 5 times more common than duodenal ulcers.

f.  Ulcers are most likely to occur in the first 1–3 months of NSAID use.

g.  Risk factors for NSAID-associated PUD include the following:

(1)  History of prior PUD

(2)  Age > 65 years

(3)  High-dose NSAID therapy

(4)  Concomitant use of aspirin (low or high dose), corticosteroids, or anticoagulants.

(5)  Concurrent H pylori infection

h.  NSAIDs may be nonselective, inhibiting both COX-1 and COX-2, or selective, inhibiting only COX-2.

(1)  Selective COX-2 inhibitors have less GI toxicity.

(2)  However, several selective COX-2 inhibitors increase the risk of myocardial infarction and several have been withdrawn from the market. Celecoxib is still available.

(3)  Alternate strategies to decrease the risk of NSAID-related PUD include concurrent use of proton pump inhibitors (PPIs) or misoprostol.

3.  Zollinger-Ellison syndrome is a rare cause of PUD that results from a tumor secreting gastrin, leading to hypersecretion of HCL in the stomach.

C.  Complications

1.  Bleeding, which can vary from massive hemorrhage (with hematemesis and melena or hematochezia) to occult, chronic, subtle bleeding with iron deficiency anemia (see Chapter 19, GI Bleeding).

2.  Perforation

3.  Weight loss

Evidence-Based Diagnosis

A.  History and physical exam

1.  Pain is not a good predictor of PUD.

a.  Ulcers are often asymptomatic and symptoms are more likely with non–NSAID-associated ulcers.

(1)  60% of NSAID-associated ulcers are asymptomatic.

(2)  25% of non-NSAID ulcers are asymptomatic.

b.  Pain often reflects nonulcer dyspepsia rather than PUD.

(1)  Less than one-third of patients with epigastric discomfort have PUD.

(2)  Among patients undergoing endoscopy, patients with nonulcer dyspepsia have more severe and numerous symptoms than patients with PUD.

c.  Surprisingly, several clinical predictors are not good at discriminating ulcer from nonulcer dyspepsia including:

(1)  Response to antisecretory therapy

(2)  Epigastric tenderness

(3)  The quality of the pain

2.  Best predictors of PUD are a history of NSAID use and H pylori infection (Table 32-5).

Table 32-5. Prevalence of PUD in patients with dyspepsia.

When considering PUD, it is critical to ask the patient about NSAID use, including both over-the-counter and prescription analgesics, as well as low-dose aspirin.

3.  The first sign of PUD may be a life-threatening complication (hemorrhage or perforation): > 50% of patients with serious to life-threatening complication had no prior symptom.

4.  Unintentional weight loss may be a sign of a benign gastric ulcer.

a.  31–55% of patients with benign gastric ulcer noted weight loss.

b.  ~50% lost 10–20 lbs; 21% lost > 20 lb

c.  PUD is found more often in patients undergoing esophagogastroduodenoscopy (EGD) for weight loss than for dyspepsia.

A significant number of patients with NSAID-induced ulcers do not experience pain. Anemia, GI bleeding, early satiety, or weight loss can be the only symptom of PUD.

B.  Laboratory studies

1.  H pylori testing

a.  Eradication markedly decreases recurrence of PUD from 60–100% to < 20%. All patients with documented PUD, whether or not they are taking NSAIDs, should be tested for H pylori.

b.  Patients with a prior history of PUD who have not previously been treated for H pylori should also be tested.

c.  Testing for H pylori is also recommended for patients with dyspepsia. Eradication is recommended in all infected patients.

d.  Options for diagnosing H pylori infection include invasive and noninvasive testing.

(1)  Noninvasive

(a)  Urea breath tests and H pylori stool antigen are preferred in patients not undergoing EGD.

(b)  The stool antigen test is much more widely available than the urea breath test and is used much more commonly in practice.

(c)  Serology cannot distinguish prior to current infection and is not recommended in most cases.

(2)  Invasive

(a)  Rapid urease test and biopsy with microscopic examination are preferred in patients undergoing EGD, although this is not commonly indicated as a first step in patients < 60 years.

(b)  Recent PPIs (within 2 weeks) or recent antibiotics (within 4 weeks) may cause false-negative urease tests.

(c)  Active bleeding decreases the sensitivity of rapid urease tests. Patients with bleeding and negative rapid urease tests and negative histology should undergo urea breath tests several weeks after completing PPI therapy.

(3)  Test characteristics are shown in Table 32-6.

Table 32-6. Test characteristics for detecting Helicobacter pylori infection.

2.  Ulcer diagnosis

a.  EGD is more sensitive than upper GI series (92% vs 54%) and is useful to rule out other serious pathology.

b.  Recent guidelines stratify the approach to EGD by patient age

(1)  EGD is recommended in patients aged 60 years or older with dyspepsia to rule out serious conditions, including cancer.

(2)  EGD is not usually recommended in patients younger than 60 years with dyspepsia.

(a)  EGD can usually be deferred in favor of noninvasive H pylori testing and presumptive PPI therapy.

(b)  This includes patients younger than 60 years with “alarm features” (anemia, weight loss, dysphagia or persistent vomiting).

i.  Alarm features have relatively poor overall operating characteristics for the presence of organic pathology (gastritis, PUD, or neoplasia).

ii.  LR+ of 2.74

iii.  Coupled with the very low prevalence of gastric cancer in patients younger than 60 years (without a family history or personal risk factor placing them at higher risk), endoscopy is unlikely to be a cost-effective strategy.

(c)  EGD should be considered in patients younger than 60 years with weight loss ≥ 20 pounds, rapidly progressive dysphagia, or a combination of alarm features.

(d)  This guideline does not apply when alarm symptoms are present in the absence of dyspepsia; in this case, alarm symptoms should be pursued more aggressively.

(3)  A diagnostic approach to dyspepsia is illustrated in Figure 32-3.

Figure 32-3. Diagnostic approach: dyspepsia.

Treatment

A.  The 3 components of therapy for PUD include eradication of H pylori, if present; discontinuation of NSAIDs, if possible; and use of PPIs. In addition, gastric ulcers warrant biopsy to rule out malignancy.

B.  Regardless of the cause of the ulcer, and the presence or absence of bleeding, PPIs dramatically suppress acid secretion and are the mainstay of therapy. For patients infected with H pylori, PPIs are given during the course of antibiotic therapy, longer for larger ulcers (> 1–2 cm) and in patients with complications or persistent symptoms.

C.  H pylori eradication

1.  Multiple options: Ideal initial therapy is controversial and recommendations are likely to evolve due to changing resistance patterns.

2.  Confirming eradication

a.  Increased incidence of H pylori resistance has led to the recommendation for posttreatment testing to confirm eradication in patients with documented PUD or those with recurrent dyspepsia.

b.  Appropriate tests include the stool antigen or urea breath tests. Testing should be delayed until 4–6 weeks after completing therapy because both PPIs and antibiotics can cause false-negative test.

D.  NSAID-associated ulcers

1.  Prevention

a.  A variety of options are available to reduce the risk of NSAID-associated PUD, including minimizing the NSAID dose; avoiding concomitant aspirin, corticosteroids, and oral anticoagulants when possible; using COX-2 selective inhibitors in patients without cardiovascular risk; and adding gastric protection with PPIs or misoprostol.

b.  PPIs

(1)  Very effective

(2)  Reduce the ulceration rate in high-risk patients (those over 65 years or with prior ulcers) from 17% to 5% as well as the rate of GI bleeding (relative risk 0.13).

c.  Misoprostol

(1)  Similar efficacy to PPIs

(2)  Requires dosing 4 times daily and is frequently associated with diarrhea, limiting its usefulness.

d.  H2-receptor antagonists are less effective than PPIs.

e.  COX-2 inhibitors

(1)  Reduce the rate of ulcers compared with nonselective NSAIDs (relative risk 0.26) but appear less effective than PPIs (when combined with nonselective NSAIDs).

(2)  Increase the risk of cardiovascular events

(3)  The gastric protection of COX-2 inhibitors is eliminated in patients on concurrent low-dose aspirin.

f.  Ineffective strategies for preventing NSAID-associated gastric ulcers include sucralfate and enteric-coated aspirin.

g.  Patients with recent PUD-related bleeding

(1)  Continuing NSAIDs (nonselective with a PPI or COX-2 selective) results in high complication rates.

(2)  The combined use of PPIs with COX-2 inhibitors was safe in patients with documented ulcer bleeding who did not have H pylori infection.

h.  Current guidelines for ulcer prevention:

(1)  All patients: If prior PUD, test and eradicate H pylori.

(2)  Use lowest dose of NSAID possible for the briefest period.

(3)  Prophylactic therapy is stratified based on the patient’s risk factors for PUD

(a)  Risk factors include age > 65; high-dose NSAID therapy; prior history of uncomplicated PUD; concomitant aspirin, corticosteroids, or anticoagulants

(b)  PPIs or misoprostol are recommended for patients with 1–2 risk factors

(c)  For patients with > 2 risk factors or recent or complicated PUD:

i.  Requiring low-dose aspirin (for CAD or CVD): Avoid all other NSAIDs (including COX-2 inhibitors) and use PPI or misoprostol.

ii.  Not requiring low dose aspirin: Avoid NSAIDs if possible or alternatively use COX-2 inhibitor with PPI or misoprostol.

2.  Documented ulcers

a.  Test for H pylori infection and eradicate if present.

b.  Discontinue NSAIDs if possible, initiate PPI therapy.

c.  Strategies for patients who require continuation of NSAIDs (even low-dose aspirin) should include:

(1)  Continue PPI therapy for the duration of NSAID (even after H pylori eradication).

(2)  Minimize the dose and duration of NSAIDs.

(3)  Avoid certain high-risk nonselective NSAIDs, such as ketorolac, piroxicam, indomethacin, diclofenac, sulindac, and naproxen, all of which increase the relative risk of PUD.

E.  Follow-up endoscopy

1.  Many authorities recommend posttreatment follow-up endoscopy for patients with documented gastric ulcers to rule out an underlying gastric cancer missed on initial endoscopy.

2.  This will have the greatest yield in high-risk groups (Asians, Hispanics, patients over 55 years, and those with a history of H pylori infection without recent NSAID use).

3.  Follow-up endoscopy is particularly important in patients with gastric ulcers in whom adequate biopsies were not obtained during the initial endoscopy.

MAKING A DIAGNOSIS

Given the absence of pain, Mr. O’s history of NSAID use, the early satiety, and weight loss convince you to order an EGD.

The EGD reveals 2 gastric ulcers 1.5 cm in size. Pathology reveals organisms consistent with H pylori.

Have you crossed a diagnostic threshold for the leading hypothesis, gastric ulcer? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

You conclude that the likely cause of Mr. O’s weight loss is gastric ulcer. You elect to initiate therapy without further testing.

Altogether, malignant and nonmalignant GI diseases are the cause of unintentional weight loss in 28% of patients. The yield of EGD in patients with unintentional weight loss is 12–44%. EGD should be considered in the evaluation of patients with unexplained weight loss especially in the absence of epigastric pain (which is counterintuitive).

CASE RESOLUTION

Mr. O received eradication therapy, a PPI, and stopped the ibuprofen. Three months later, his appetite is excellent and his weight is approaching baseline. He is advised to use acetaminophen for his arthritis pain and to perform nonimpact physical activities.

CHIEF COMPLAINT

PATIENT

Mr. A. is a 62-year-old man who complains of recent weight loss. He reports that he has lost 15 pounds over the last 6– 9 months, and that his clothes no longer fit. He does not have diarrhea but does have abdominal bloating and is having several large stools a day that are difficult to flush. He reports that his appetite is not what it used to be but attributes that to his recent separation from his wife. He confides that they have not gotten along for years. She seemed to blame everything on his drinking, but he assures you that alcohol was definitely not a problem.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

The first pivotal step in evaluating Mr. A’s unintentional weight loss is to verify the weight loss. This is clearly established by his history and a review of his medical records. The second step looks for symptoms suggestive of malabsorption and although he denies frank diarrhea, his large frequent stools raise the possibility of GI diseases associated with malabsorption. The third pivotal step differentiates weight loss due to decreased caloric intake or absorption from that due to increased caloric expenditure and the fourth (and pivotal) step reviews the history, physical exam, and laboratory studies to look for other clues that might suggest a diagnosis. Mr. A’s social history raises several possibilities. First, you suspect that his drinking is a problem and might be contributing to his weight loss. Alternatively, he may be more depressed than he acknowledges or simply adjusting to lifestyle changes precipitated by his separation. His difficult to flush stools also suggests one of a variety of causes of malabsorption. Table 32-7 lists the differential diagnosis.

Table 32-7. Diagnostic hypotheses for Mr. A.

On further questioning, Mr. A reports that he drinks “two or so” alcoholic beverages a night. He proudly states that he has never missed work due to a hangover and never drinks before noon. When you ask him how much alcohol he uses when preparing each drink and whether anyone else has commented on his drinking, he gets defensive and reminds you he is here because he is losing weight.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Mr. A’s defensiveness increases your suspicion of an alcohol use disorder. You wonder how much alcohol consumption is normal, what would constitute problem drinking, and how to evaluate him more thoroughly for alcohol use disorder.

Leading Hypothesis: Alcohol Use Disorder

Textbook Presentation

Alcohol intake varies from low-risk use to risky use, problem drinking, abuse, and finally alcohol dependence. Patients with alcohol use disorders present along a continuum, from the functioning executive to the homeless alcoholic. Psychosocial complications include job loss, marital difficulties, loss of driving license, and violent behavior. Medical complications may include accidental injury, pancreatitis, gastritis, cirrhosis, vitamin deficiency, cardiomyopathy, hypertension, malnutrition, weight loss, and death. Weight loss may be multifactorial secondary to decreased caloric intake during intoxication or due to alcohol-related illnesses (gastritis, pancreatitis, cirrhosis). Alcohol use disorders may be difficult to recognize early, when intervention may prevent progression.

Disease Highlights

A.  Alcohol is responsible for 79,000 deaths per year in the United States and alcohol misuse disorders affect 9% of the US population. Causes of alcohol-related deaths include motor vehicle accidents, drownings, suicides, cirrhosis, and an increased risk of several cancers (esophageal, breast, pharyngeal, laryngeal, and hepatocellular cancer).

B.  Women are more likely to deny alcohol-related problems and to have associated eating disorders, depression, and panic disorders.

C.  37% of adults with alcohol abuse or dependence have concomitant mood or personality disorders.

D.  Categories and definitions of patterns of alcohol use (1 drink is defined as 12 g of alcohol or 1.5 oz of liquor, 5 oz of wine, or 12 oz of beer)

1.  Risky use: Prevalence 4–29%. Criteria:

a.  Men ≤ 65 years: > 14 drinks/wk or > 4 drinks per occasion

b.  Women of any age and men > 65 years: > 7 drinks/wk or > 3 drinks per occasion

2.  Hazardous drinking: At risk for consequences from alcohol

Evidence-Based Diagnosis

A.  The USPSTF recommends screening all adults for alcohol misuse annually.

1.  The 3 recommended screening tools are the 10 question Audit tool, the 3 question Audit-C tool (found at http://www.integration.samhsa.gov/clinical-practice/screening-tools\#drugs) or a single question “How many times in the past year have you had 5 or more drinks per day (for men) or 4 (for women and persons over 65 years).

2.  An Audit score of ≥ 4 in men (≥ 3 in women) has a sensitivity of 84–85%, specificity of 77–84%; LR+, 4.2; LR–, 0.2.

3.  A single positive response to the 1 question tool has a sensitivity of 82%, specificity of 79% for unhealthy use; LR+, 3.9; LR–, 0.23.

B.  The DSM-5 defines alcohol use disorder as “a problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following” over a 1-year period:

1.  Alcohol often consumed in larger amounts or over a longer period than was intended.

2.  Persistent desire or unsuccessful efforts to cut down or control alcohol use.

3.  A great deal of time spent obtaining, using, or recovering from alcohol.

4.  Craving, or strong desire to use alcohol.

5.  Recurrent use resulting in failure to fulfill major role or obligations.

6.  Continued use despite social or interpersonal problems caused by or exacerbated by alcohol.

7.  Important social, occupational, or recreational activities are given up or reduced because of alcohol use.

8.  Continued use despite knowledge of a physical or psychological problem caused by or exacerbated by alcohol.

9.  Tolerance

10.  Withdrawal

C.  A variety of clinical clues can suggest alcohol misuse, including injury; resistant hypertension; family, work, or legal problems; violence; depression; substance abuse; chronic pain; anemia; thrombocytopenia; or a family history of alcoholism.

D.  Laboratory abnormalities (Table 32-8)

Table 32-8. Accuracy of detecting unhealthy drinking using laboratory tests.

1.  A variety of laboratory abnormalities may be seen in patients with heavy alcohol use, including an elevated AST, GGT, or macrocytosis.

2.  Elevated levels may increase the suspicion of alcoholism but are insensitive and should not be used to rule out the diagnosis. That is, patients with alcohol use disorder may (and frequently do) have normal liver enzymes and complete blood counts.

3.  The sensitivity increases in patients with alcohol dependency in whom the diagnosis is increasingly obvious.

E.  Patients in whom risky drinking is suspected should be asked about symptoms that suggest the alcohol use disorder, health problems related to alcohol use (gastritis, pancreatitis, alcoholic liver disease [including alcoholic hepatitis and cirrhosis], and resistant hypertension), readiness to change, and their pattern of consumption (including average number of drinks per day, maximum number of drinks per day, and days per week that they consume alcohol).

Treatment

A.  Brief (6–15 minute) multi-contact counseling interventions for persons identified with risky or hazardous drinking has been demonstrated to reduce weekly consumption, heavy drinking, traumatic injury, and death and is recommended by the USPSTF.

B.  Components of effective interventions for hazardous drinkers include:

1.  Specialty referral

2.  Feedback on clinical and laboratory assessment

3.  Comparison to drinking norms

4.  Discussion of the adverse effects of alcohol

5.  Statement of the recommended drinking limits

6.  Prescription to “Cut down on your drinking”

7.  Patient educational material (www.niaaa.nih.gov)

8.  Drinking diary

9.  Follow-up office sessions and phone contact

C.  Patients at moderate to high risk for alcohol withdrawal (a potentially fatal condition) and those with concomitant psychiatric disorders (especially suicidal ideation) or unstable home environments should be hospitalized in a detoxification unit. (See Chapter 11, Alcohol Withdrawal.)

D.  Patients with alcohol use disorder should also receive a referral to a specialty treatment center, pharmacotherapy, and support groups.

E.  Relapse prevention: Several options

1.  Alcoholics Anonymous (AA), a 12-step program that has demonstrated effectiveness in increasing the rate of abstinence at 3 years from 43% to 62%

2.  Motivational enhancement therapy

3.  Therapy to develop cognitive-behavioral coping skills

4.  Naltrexone, acamprosate, and disulfiram have reduced drinking in patients with alcohol dependence. Pharmacotherapy is most effective when combined with behavioral support.

5.  Treatment of depression and other mental illness, if present.

MAKING A DIAGNOSIS

Mr. A’s history of “two or so” drinks per night suggest at-risk drinking. Furthermore, his marital separation, while possibly multifactorial, raises the possibility of alcohol abuse that is interfering with his relationships. You ask Mr. A the screening question if he has had 5 or more drinks on any day in the last year.

Mr. A reports that he probably drinks that much at least once a month when he is “partying.”

Mr. A.’s response increases your concern. You elect to administer the Audit score questionnaire.

Mr. A scores 15 (out of a possible 40). He acknowledges that he tried to cut down while he was married, but since his separation, he no longer feels that restraint. He acknowledges that occasionally he hears funny stories about himself from these parties that he cannot recollect (amnesia). Mr. A also reluctantly reports that he received 2 citations for driving while intoxicated within the past year. He feels mildly guilty about this but assures you he knows better than to make that mistake again. He reiterates that he has never missed work due to his drinking but did miss several family events because he was “partying.”

Mr. A’s Audit score, marital difficulties, blackouts, tickets for driving while intoxicated, missed social events, and continued use despite interpersonal difficulties is diagnostic of an alcohol use disorder. You elect to check a CBC and a liver panel.

The CBC shows macrocytosis and the liver panel shows a mildly elevated AST and ALT. The elevation in AST is more marked than the elevation in ALT, a pattern commonly seen in alcoholic liver disease.

Clearly, Mr. A suffers from alcohol abuse. This may be the sole cause or a contributing cause of his unintentional weight loss. You elect to initiate a treatment plan and reevaluate him once he is abstinent.

CASE RESOLUTION

You have a frank discussion of the issues with Mr. A. You acknowledge that his marital difficulties are complex but that many features of his alcohol use suggest an alcohol use disorder. The missed family gatherings, alcoholic blackouts, tolerance, tickets for driving while intoxicated, and abnormal blood test results all suggest this is a serious medical problem. Mr. A confides that he is frightened to go “cold turkey,” because he feels shaky and agitated whenever he stops drinking. You suggest admission to a detoxification unit. Mr. A listens carefully and agrees to be admitted to the detoxification unit.

FOLLOW-UP OF MR. A

Two months later, Mr. A returns to your office. His mood is clearly better. He proudly reports that he is “on the wagon” and feeling better. He attends AA meetings 5–7 nights per week. However, he remains concerned about his weight. He reports that his appetite is better and he is eating well but has not regained any weight.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

Mr. A’s response to your intervention is rewarding. It is surprising that his weight is not improving, particularly in light of his improved appetite. During his previous visit, he mentioned difficult to flush, large stools and you wonder if part of his weight loss is secondary to malabsorption. He continues to have these large, difficult to flush stools. You revisit the common causes of malabsorption (Table 32-9 and Figure 32-4).

Table 32-9. Differential diagnosis of chronic diarrhea organized by mechanism.

Figure 32-4. Diagnostic approach: malabsorption and diarrhea.

RANKING THE DIFFERENTIAL DIAGNOSIS

Mr. A’s history of difficult to flush stools but no diarrhea is more suggestive of chronic malabsorption than a chronic infectious diarrhea. You review those causes carefully and consider chronic small bowel disease (eg, inflammatory bowel disease [IBD], bacterial overgrowth, celiac disease) and chronic pancreatitis.

Mr. A has never been diagnosed with acute pancreatitis. He does remember multiple episodes of abdominal pain over the years following a night of binging. He did not seek medical care but remained at home drinking only clear fluids for several days until the pain subsided. He denies any history of bowel surgery, family history of IBD, or hematochezia.

Mr. A’s history of alcohol abuse and recurrent pain leads you to suspect that he may have chronic pancreatitis. This becomes the leading hypothesis.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: Chronic Pancreatitis

Textbook Presentation

Patients typically seek medical attention for long-standing postprandial abdominal pain. Frequent, loose, malodorous bowel movements are common, and weight loss occurs. Patients may note that several flushes are required to clear the toilet. A prior history of alcoholism and acute pancreatitis are clues to the diagnosis.

Disease Highlights

A.  Usually secondary to recurrent acute pancreatitis, primarily from alcohol abuse (70% of adult cases). Less common causes in adults include cystic fibrosis, hereditary pancreatitis, ductal obstruction (ie, stones, tumor), tobacco use, autoimmune disease, hypercalcemia, and hypertriglyceridemia.

B.  Progressive pancreatic destruction results in both exocrine and endocrine insufficiency.

C.  Manifestations include

1.  Chronic, disabling, mid-epigastric postprandial pain is very common (80–100% of patients) and a major cause of morbidity. The pain may radiate to the back and be relieved by sitting forward.

2.  Weight loss secondary to anorexia and malabsorption with steatorrhea

3.  Steatorrhea

a.  Defined as fat malabsorption ≥ 14 g/day (nl ≤ 7 g/day fecal fat on 75–100 g fat diet. Patients with primarily watery diarrhea may excrete up to 13 g/day of fecal fat).

b.  Manifestations include difficult to flush oily stools and weight loss. Elderly patients may not have diarrhea.

c.  Floating stools are not specific for steatorrhea. Bacterial gas may also cause stools to float.

d.  Diarrhea may develop secondary to bacterial overgrowth, which develops in 40% of patients with chronic pancreatitis.

4.  Diabetes may develop due to the concomitant destruction of islet cells.

a.  Ketoacidosis is rare.

b.  Hypoglycemia is common due to loss of glucagon-producing pancreatic alpha cells.

5.  Complications include pseudocysts, necrosis, obstruction of the common bile duct or duodenum, and pancreatic ascites (usually from a ductal disruption). Splenic vein thrombosis may also develop, leading to gastric varices.

6.  Pancreatic cancer develops in 4% of patients but no consensus on screening.

Evidence-Based Diagnosis

A.  One study reported unintentional weight loss and diarrhea in 68%, and bloating in 30%. Diabetes was found in 28%.

B.  Laboratory tests

1.  Manifestations may be structural (pancreatic calcifications, atrophy, and ductal dilatation) or functional (with pancreatic insufficiency).

2.  While patients with advanced disease typically have both structural and functional changes, patients with early disease may have either just structural changes (diagnosed on imaging) or just functional abnormalities (diagnosed with secretin testing).

3.  The gold standard is biopsy, which is rarely performed.

4.  Precise sensitivity and specificity are difficult to estimate due to the (1) infrequency of biopsy, (2) difficulty interpreting results in patients with discordant structural and functional changes, and (3) variation of sensitivity and specificity with stage of the disease.

5.  Structural changes are typically diagnosed with CT scan, endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasonography (EUS), or magnetic resonance cholangiopancreatography (MRCP).

6.  CT scan with contrast

a.  Often performed first given availability, although MRCP, EUS, and ERCP have similar operating characteristics.

b.  CT manifestations include ductal calcifications (74–90% sensitive, 85% specific), ductal dilatations, and pancreatic atrophy. Pancreatic fluid collections, necrosis, or tumors can also be seen.

c.  Pancreatic calcifications are often assumed to be specific for chronic pancreatitis but have also been reported in a variety of pancreatic tumors.

7.  ERCP is invasive and typically reserved for patients in whom it might be therapeutic (ie, stenting) (sensitivity, 75– 95%; specificity ≈ 90%).

8.  Secreting stimulation functional assessment

a.  Typically the most sensitive tests in chronic pancreatitis with excellent negative predictive value.

b.  Time consuming, labor intensive, invasive, and not widely available

c.  Secretin is administered and the pancreatic secretions collected in the duodenum. Peak bicarbonate concentration is measured.

d.  Cholecystokinin stimulation of the acini (to produce lipase) has also been used.

e.  Greatest utility may be in patients with early chronic pancreatitis in whom imaging studies may be normal.

9.  EUS: Using secretin as gold standard, 71% sensitive, 92% specific; LR+, 7.9; LR–, 0.32

10.  Other less diagnostic tests

a.  Amylase and lipase are often normal or slightly elevated.

b.  Abdominal radiographs may reveal pancreatic calcifications. Sensitivity is only 30%.

c.  Routine abdominal ultrasound is 60–70% sensitive and 80–90% specific.

11.  MRCP with secretin (used to enhance visualization of the pancreatic ducts) is being evaluated for the diagnosis of chronic pancreatitis.

12.  Fecal elastase may be low (< 200mcg/g) in patients with chronic pancreatitis, but false-positives and false-negatives exist. Pooled sensitivity 77%, specificity 88% (LR+, 6.4; LR–, 0.26) when compared to secretin testing. In patients with low risk for exocrine insufficiency, normal value rules out pancreatic exocrine insufficiency; in patients at higher risk, false-negative rate may be as high as 10%.

Treatment

A.  Abstinence from tobacco and drinking alcohol is vital (but not universally effective at halting progression).

B.  Pain management

1.  Exclude other causes of increasing or persistent pain

2.  NSAIDs, TCAs, and opioids are often used. Opioid dependence is a common problem.

C.  Pancreatic enzymes

1.  Can decrease pain and improve nutritional status.

2.  Give with meals and low-fat diets (< 20 g/day).

3.  Nonenteric-coated enzymes may provide superior pain relief.

4.  Coadministration of PPIs is recommended to prevent the inactivation of the enzymes.

D.  Patients with diabetes are at risk for hypoglycemia with therapy (due to concomitant loss of glucagon production. Diabetes should be treated cautiously and metformin should be avoided in patients with alcohol use disorder.

E.  ERCP with stenting, and surgery are useful in selected patients to relieve obstruction and pain.

F.  Treatment of peripancreatic fluid collections and pancreatic necrosis require specialty consultation and often require endoscopic drainage.

G.  Total pancreatectomy with auto-islet transplantation may be considered in specialty centers for younger patients with chronic pancreatitis and severe functional limitation.

MAKING A DIAGNOSIS

A CT scan with contrast of the abdomen reveals multiple areas of pancreatic calcifications consistent with chronic pancreatitis. Fecal elastase is 84 mcg/g, suggestive of pancreatic insufficiency.

Have you crossed a diagnostic threshold for the leading hypothesis, chronic pancreatitis? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: Bacterial Overgrowth

Textbook Presentation

Classically, patients have previously undergone GI surgery that resulted in some type of surgical blind loop that allows for bacterial multiplication. Patients may experience long-standing diarrhea, bloating, and weight loss.

Disease Highlights

A.  Mechanism of diarrhea is multifactorial.

1.  Bacteria digest carbohydrates producing gas and osmotically active byproducts promoting an osmotic diarrhea.

2.  Bacteria and their fatty acid byproducts injure mucosa and contribute to diarrhea.

3.  Mucosal injury can lead to lactase deficiency.

4.  Bacterial deconjugation of bile salts interferes with fat absorption as well as the absorption of fat-soluble vitamins.

B.  Etiologies

1.  Stasis

a.  Strictures (surgical, Crohn disease, radiation enteritis)

b.  Anatomic abnormalities (surgical blind loops or diverticula)

c.  Dysmotility (diabetic autonomic neuropathy, scleroderma, opioid use)

d.  Chronic pancreatitis (obstruction or opioid therapy can promote stasis).

2.  Abnormal small to large intestine connections (ie, fistula) or resection of ileocecal valve (allows retrograde colonization from heavily colonized colon into ileum)

3.  Achlorhydria (ie, PPI therapy or autoimmune)

4.  Miscellaneous (pancreatic insufficiency, cirrhosis up to 60% of patients, end-stage renal disease)

C.  Bacteria may utilize B12, leading to B12 deficiency.

D.  Unusual complications include tetany (due to hypocalcemia) and night blindness due to vitamin A deficiency.

Evidence-Based Diagnosis

A.  Healthy older patients may also have bacterial overgrowth without any symptoms, making diagnosis difficult.

B.  Gold standard is quantitative jejunal aspirates demonstrating > 105 bacteria/mL.

C.  A variety of tests detect bacterial byproducts in exhaled breath as an aid to diagnosis. Since bacteria normally reside in the colon, but only in low levels in the small intestine, early peaks in the concentration of these byproducts suggest small intestinal bacterial overgrowth. False-positives and false-negatives occur when other conditions increase or decrease bowel transit time, respectively. Antibiotics can interfere with the breath tests.

1.  D xylose breath test is usually abnormal secondary to bacterial digestion of xylose-releasing radiolabeled C14.

a.  Sensitivity, 30–95%; specificity, 89–100%.

b.  Avoid in fertile women.

2.  Hydrogen breath tests measure exhaled bacterial hydrogen production after patients ingest sugar.

a.  Their accuracy is similar to the xylose tests and avoids radioactivity.

b.  Some bacteria produce methane, and this measurement may increase accuracy.

D.  Consider bacterial overgrowth if upper GI series demonstrates hypomotility, obstruction, or diverticula.

E.  Weight loss may occur without diarrhea.

F.  Therapeutic trials of antibiotics may be necessary.

Treatment

A.  Eliminate drugs that reduce intestinal motility (especially opioids) or reduce gastric acidity.

B.  A variety of oral antibiotics have been used for 7–10 days. Rotating courses of antibiotics have been used in some patients. Rifaximin is a minimally absorbed antibiotic that has been useful.

C.  Correct calcium as well as vitamin A, D, K, and B12 deficiency.

D.  Minimizing carbohydrates, especially lactose, can be helpful.

Alternative Diagnosis: Inflammatory bowel disease (IBD)

Crohn disease is a transmural process that may affect the entire GI tract from mouth to anus whereas ulcerative colitis is a mucosal disease limited to the colon. Both occur more often in patients of Jewish descent and among patients with a family history of IBD. Extraintestinal manifestations of IBD may include uveitis, erythema nodosum, pyoderma granulosum, large or small joint peripheral arthritis, ankylosing spondylitis, primary sclerosing cholangitis, secondary amyloidosis, and venous thromboembolism. Chronic colitis increases the risk of colon cancer in proportion to the amount of the colon involved and the duration of disease.

1. Crohn Disease

Textbook Presentation

Common complaints include chronic abdominal pain, diarrhea, fever, weight loss, enterocutaneous fistulas, and acute abdominal pain (which can mimic acute appendicitis).

Disease Highlights

A.  Patchy, transmural inflammation can lead to fistula formation, phlegmon, strictures with obstruction, perforation, abscess formation, and peritonitis.

B.  Manifestations

1.  The disease course is characterized by exacerbations and remissions.

2.  Typically presents with insidious onset of symptoms of weight loss, diarrhea, and abdominal pain, although occasionally acute symptoms (eg, acute toxic megacolon or acute ileitis mimicking acute appendicitis) are the presenting manifestations of Crohn disease.

3.  Can involve any part of the GI tract with normal “skip areas” between involved areas. At presentation:

a.  ≈ 20% of patients had ileitis, 45% ileocolitis, and 33% colitis. Upper GI involvement can occur.

b.  ≈ 27% had strictures or perforation

4.  Perianal or rectal fistulas occur in 14–37% of patients.

5.  Diarrhea (with or without gross bleeding), weight loss, abdominal pain, and fever are common.

6.  Diarrhea may occur due to

a.  Small bowel disease impairing absorption

b.  Ileal disease

(1)  May decrease bile salt absorption, allowing bile salts into the colon, which cause irritation and diarrhea.

(2)  Severe bile salt malabsorption also causes bile salt deficiency and steatorrhea.

c.  Bacterial overgrowth secondary to strictures

7.  Obstruction due to strictures

8.  Fistulas may be enterocutaneous fistulas (most commonly perianal), enterovesicular (resulting in polymicrobial urinary tract infections), enterovaginal, or enteroenteric (bowel to bowel).

9.  B12 deficiency (secondary to ileal disease)

10.  Calcium oxalate kidney stones

a.  Normal GI oxalate absorption is limited by intraluminal intestinal binding of oxalate to calcium.

b.  Malabsorption increases intraluminal fat. Intraluminal fat binds intraluminal calcium decreasing calcium’s availability to oxalate.

c.  This leads to increased oxalate absorption.

d.  Increased oxalate absorption causes hyperoxaluria and promotes the formation of calcium oxalate kidney stones.

11.  Osteoporosis due to vitamin D deficiency, calcium malabsorption, and prolonged corticosteroid therapy.

12.  Gross bleeding is less frequent in Crohn disease than in ulcerative colitis.

13.  Aphthous ulcers

Evidence-Based Diagnosis

A.  When considering a diagnosis of Crohn disease, important historical features are changes in weight, abdominal pain, fever, a personal history of recent antibiotic or NSAID use (to consider the likelihood of C difficile– or NSAID-associated colitis), symptoms or history of extraintestinal manifestations (uveitis, arthritis, or erythema nodosum) and family history of IBD.

B.  The physical exam should include weight (and changes from prior); vital signs; and oral, abdominal, rectal, and dermatologic exams.

C.  Initial laboratory studies should include a CBC, comprehensive metabolic panel, ESR, CRP, vitamin B12, and folate.

D.  Active infection with the following organisms should be excluded in patients with diarrhea: Salmonella, Shigella, Campylobacter, Yersinia, Escherichia coli O157:H7, Giardia, C difficile, and E histolytica. C difficile has increasing prevalence (even in the absence of antibiotic use) and must be excluded prior to initiating therapy.

E.  Colonoscopy with ileoscopy and biopsy is often diagnostic but may be contraindicated in acute severe colitis.

F.  Upper endoscopy may be useful in patients with concurrent dyspepsia.

G.  Diagnostic imaging

1.  A variety of imaging techniques are available to visualize the small bowel for diagnosis and are useful in the following situations:

a.  When colonoscopy/ileoscopy fails to establish the diagnosis

b.  Evaluation of complications (ie, strictures, abscesses) and disease extent

c.  Options include ultrasound, small bowel follow through, enteroclysis, CT enterography, CT enteroclysis, MR enterography, MR enteroclysis, and capsule endoscopy.

2.  The precise role of imaging studies is not yet defined. Local expertise and availability may guide choices.

a.  MR enterography

(1)  Avoids radiation

(2)  Can detect abscesses

(3)  May distinguish fibrotic from inflammatory strictures

(4)  Recommended as the preferred technique

b.  CT

(1)  Widely available

(2)  Can detect abscesses

(3)  Associated with radiation risks (which may be of particular importance in young patients needing serial examinations)

(4)  Requires IV contrast with risk of hypersensitivity reactions and renal complications.

c.  Capsule endoscopy

(1)  Can visualize aphthous ulcers not visible on MRI or CT

(2)  Some studies suggest improved sensitivities over MR and CT

(3)  Capsules may get lodged in strictures.

(4)  Guidelines suggest ruling out strictures prior to capsule endoscopy with either small bowel follow through, CT enterography, or MR enterography.

(5)  A capsule that auto-dissolves has been developed.

d.  Ultrasound is inexpensive but operator dependent and cannot provide a comprehensive evaluation of the bowel.

Treatment

A.  Therapeutic goals include the induction and maintenance of remission.

1.  Options include 5-aminosalicylic acid (5-ASA), budesonide or conventional corticosteroids, 6-mercaptopurine (6MP), methotrexate, antitumor necrosis factor (TNF) therapy, cyclosporine, tacrolimus, and natalizumab.

2.  5-ASA and corticosteroids may be given systemically or topically (as enemas or suppositories).

B.  Antibiotics are often necessary for bacterial overgrowth, peritonitis, or abscesses (which may also require drainage).

C.  It is vital to rule out concomitant infection with an enteric pathogen in a patient presenting with a flare of IBD. Further, cytomegalovirus coinfection may be a factor in many flares.

D.  Smoking cessation is associated with a 65% reduction in relapse.

E.  Adjunctive therapy

1.  Treat lactose intolerance if present.

2.  Assess and replete vitamin B12, folate, vitamin D, zinc, iron, and calcium as necessary.

3.  Total parenteral nutrition may be necessary in patients unable to maintain adequate nutrition, although this is uncommon and should generally be avoided when possible.

4.  Bile acid resins for patients with watery diarrhea and ileal disease.

5.  Periodic colonoscopy to monitor for colon cancer in patients with colonic involvement.

6.  Surgery

a.  50% of patients require surgery in the first 10 years.

b.  Not curative. High rate of recurrence following surgery (10–15%/year clinical recurrence, 80% endoscopic recurrence).

c.  Indications include the management of massive hemorrhage, fulminant colitis, abscesses, peritonitis, obstruction, or disease refractory to medical therapy.

7.  Avoid NSAIDs and opioids if possible.

8.  Vaccinations

a.  Patients should receive influenza, pneumococcal, and human papillomavirus vaccines according to published recommendations.

b.  Hepatitis B vaccination is recommended in the nonimmune patients prior to immunosuppressive or anti-TNF therapy.

c.  Live vaccines (Bacillus Calmette-Guérin [BCG]; measles, mumps, and rubella [MMR]; oral polio; live typhoid; and varicella) should be avoided in patients taking immunosuppressants, including corticosteroids.

Ulcerative Colitis

Textbook Presentation

Typically, bloody diarrhea and fecal urgency are the presenting symptoms. Like Crohn disease, the clinical course is typically one of exacerbations and remissions.

Disease Highlights

A.  Primarily mucosal disease. (Occasionally, severe inflammation may extend deeper, involving muscular layers resulting in dysmotility and toxic megacolon.)

B.  Strictly limited to colon, in contrast to Crohn disease.

C.  Starts at rectum and proceeds proximally in a continuous fashion; may be limited to rectum or involve rectosigmoid or entire colon. Rectal sparing suggests another disease (ie, Crohn disease).

D.  Decreased risk among smokers (in contrast to Crohn disease)

E.  Anemia, fever, and increasing diarrhea are seen with more extensive disease.

F.  Complications

1.  Massive hemorrhage (rare)

2.  Anemia

3.  Toxic megacolon

4.  Stricture

5.  Colon cancer

a.  The cancer risk is increased except in patients with just proctitis or very distal colitis.

b.  Increased risk of colon cancer begins 7–8 years after the onset of disease.

Evidence-Based Diagnosis

A.  Sigmoidoscopy or colonoscopy demonstrates loss of vascular markings, erythema, friability, and exudates in a continuous fashion extending from the rectum proximally.

B.  Biopsy specimen reveals crypt abscesses, branching crypts, and glandular atrophy.

C.  Patients should be asked about travel history or recent antibiotic use that increases the likelihood of bacterial gastroenteritis or C difficile colitis. Stool samples should be sent to exclude acute infectious processes (Salmonella, Shigella, Campylobacter, E coli O157:H7, C difficile, E histolytica). Biopsy is often done to exclude cytomegalovirus.

D.  The diagnosis is typically made in patients with characteristic endoscopic and pathologic findings in the absence of infection. Small bowel imaging can be also useful if Crohn disease is considered (small bowel involvement suggests Crohn disease since ulcerative colitis does not affect the small bowel).

E.  NSAIDs may cause colitis and their use as a cause of colitis should also be excluded.

Treatment

A.  Patients should be monitored for relapse regularly and asked about diarrhea, rectal bleeding, and systemic symptoms. The patient’s weight and hemoglobin should be monitored.

B.  Decisions regarding choice of therapy depend on a combination of disease location and severity.

1.  Distal disease (descending colon and beyond) can often be treated with topical preparations (suppositories or enemas). Options include topical preparations of 5-ASA or corticosteroids (suppositories, enemas, or foams) or oral 5-ASA preparations.

2.  More proximal or severe disease requires systemic therapy.

3.  Therapy is also intensified in patients with severe disease manifested by greater stool frequency, increased bleeding, systemic symptoms (fever, tachycardia, anemia, elevated CRP, and elevated ESR) or sigmoidoscopic appearance.

C.  Oral or systemic corticosteroids can be added for more severe disease or nonresponders.

D.  Cyclosporine, 6MP, and infliximab have been effective in some patients with severe, corticosteroid-refractory disease.

E.  Antibiotics may be useful in select ill patients, particularly those with toxic megacolon or peritonitis.

F.  5-ASA preparations (but not topical corticosteroids) are effective at maintaining remission. 6MP and infliximab can also be effective.

G.  Surgery (colectomy) is curative. Indications include:

1.  Patients with high-grade dysplasia, carcinoma in situ, or cancer on surveillance colonoscopy. Low-grade dysplasia should also prompt consideration for colectomy.

2.  Other severe complications including massive hemorrhage, perforation, and toxic megacolon.

3.  Intractable disease

H.  Adjuvant therapy

1.  Persistent diarrhea

a.  Test for lactose intolerance.

b.  Avoid fresh fruits, vegetables, and caffeine.

2.  Surveillance colonoscopy for colon cancer for ulcerative colitis and Crohn disease begins 8 years after diagnosis and then every 1–2 years.

3.  Supplemental iron

4.  Fish oils and nicotine (transdermal) have been demonstrated to induce remission in some patients.

5.  Total parenteral nutrition if patients are unable to maintain adequate nutrition, but this is to be avoided when at all possible.

6.  Antidiarrheals may increase the increased risk of toxic megacolon.

7.  Screen patients who have been taking corticosteroids for > 3 months for osteoporosis and provide calcium and vitamin D supplementation.

CASE RESOLUTION

Mr. A’s history and CT scan point strongly toward chronic pancreatitis. IBD is possible but unlikely. Since bacterial overgrowth can complicate chronic pancreatitis, an empiric trial of antibiotics could be given if therapy for chronic pancreatitis is unsuccessful.

Mr. A is given pancreatic enzymes to take with meals and snacks. He subsequently reports that his diarrhea and bloating are greatly improved. Six months later he is back to his baseline weight and he remains abstinent from alcohol.

REVIEW OF OTHER IMPORTANT DISEASES

Celiac Disease

Textbook Presentation

Classically, chronic diarrhea, steatorrhea, and weight loss are present. Iron and vitamin deficiencies may be seen.

Disease Highlights

A.  Occurs worldwide. Prevalence ≈ 0.5–1% in Northern Europeans; affects women 1.5 times more often than men.

B.  Develops only in persons with either the HLA-DQ2 or HLA-DQ8 haplotype.

1.  Develops in only a subset of such patients

2.  Those haplotypes expressed on antigen presenting cell surfaces can bind the deaminated gluten peptide found in wheat, rye, and barley.

3.  This triggers an abnormal immune response within the intestinal mucosa with subsequent mucosal injury, atrophy, and malabsorption.

4.  Antibodies develop to gliadin, transglutaminase (tTG), and endomysin (EMA).

C.  Clinical manifestations

1.  Usually presents between ages 10 and 40 years, although may be recognized in older patients.

2.  Symptoms precipitated by exposure to wheat, rye, or barley protein (gluten) and resolve within weeks to months on gluten-free diet.

3.  Diarrhea is seen in 27–50% of patients. Patients may also have weight loss (6–22%), unexplained iron deficiency anemia, osteoporosis, aphthous stomatitis, or abnormal liver biochemical tests; however, they also may be asymptomatic.

4.  Osteopenia and osteoporosis may develop due to vitamin D deficiency and subsequent secondary hyperparathyroidism.

5.  Strongly associated with dermatitis herpetiformis in a minority of patients, which develops secondary to antibodies against epidermal transglutaminase.

6.  Far more common in patients with trisomy 21.

7.  Increase risk of other autoimmune disorders including thyroiditis and type 1 diabetes mellitus.

8.  Patients with celiac disease are at increased risk for intestinal adenocarcinoma and enteropathy-associated T cell lymphoma.

Evidence-Based Diagnosis

A.  Diagnostic options include duodenal biopsy (the gold standard), serology, and clinical response to a gluten-free diet.

B.  Small bowel biopsy is the gold standard and useful but invasive. Strategies can help determine when biopsies are necessary.

C.  Serologic testing is highly accurate but not perfect.

1.  Tissue glutaminase antibody (IgA TTG)

a.  Very accurate: 90–98% sensitive, 95–97% specific; ≈ LR+ 24, LR– 0.06

b.  Simpler, cheaper, and less operator dependent than IgA EMA

c.  Initial test of choice

2.  Endomysial antibody (IgA EMA) also very accurate: 85–98% sensitive, 97–100% specific; LR+ 61, LR– 0.06.

3.  There are several causes of false-negative serologies, including

a.  IgA deficiency: IgG TTG antibodies or deaminated gliadin peptide antibodies can be tested when the suspicion is high and IgA levels are low or absent.

b.  Gluten-free diets: IgA TTG and IgA EMA levels fall (and may become negative) in patients on gluten-free diet. (Increasing titers in patients with celiac disease suggest dietary noncompliance.)

D.  HLA typing

1.  Virtually all patients with celiac disease express HLA-DQ2 or HLA-DQ8 heterodimers.

a.  100% sensitive but only 57–75% specific

b.  LR+, 2.3; LR−, 0

2.  Celiac disease can be virtually ruled out in patients who are negative for HLA-DQ2 or HAL-DQ8.

3.  Maybe useful in patients who instituted a gluten-free diet before evaluation in whom IgA tTG and IgA EMA antibody levels may be low due to decreased disease activity. If the patient expressed neither HLA-DQ haplotype, celiac disease could be excluded.

E.  Due to the low overall prevalence of celiac disease, positive EMA and tTG serologies do not confirm the diagnosis, despite their high specificity.

1.  The positive predictive value ranges from 29% to 76% and small bowel biopsy is necessary to confirm the diagnosis.

2.  In contrast, negative EMA and tTG serologies make the diagnosis very unlikely (negative predictive value ≈ 99%) and essentially rule out the disease.

3.  If concern remains despite a negative result, HLA typing could help completely exclude the disease.

4.  One approach is shown in Figure 32-5.

Figure 32-5. Diagnostic approach: celiac disease.

F.  Certain patients complain of gluten-related symptoms and improvement on a gluten-free diet despite negative serologies and biopsy. Such patients may have an ill-defined gluten sensitivity.

Treatment

A.  Gluten-free diet (no wheat, rye, and barley)

B.  Oats that are uncontaminated with gluten are usually tolerated in patients with celiac disease.

C.  Lactose avoidance may be necessary due to concomitant lactase deficiency.

D.  Correct iron, folic acid, vitamin B12, and vitamin D deficiencies.

E.  Pneumococcal vaccine is recommended by some experts.

F.  Corticosteroids or other immunosuppressives have rarely been necessary in patients with refractory celiac disease.

G.  Osteoporosis screening is recommended.

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