• In suspected carcinoid syndrome.
Serum Gastrin
• In Zollinger-Ellison syndrome.
Serum Calcitonin
• To rule out medullary carcinoma of the thyroid.
CLINICAL NOTES
• Two common conditions, usually associated with the passage of stool totaling < 200 g/d, must be distinguished from true diarrhea. Pseudo diarrhea, or the frequent passage of small volumes of stool with rectal urgency, and accompanies irritable bowel syndrome or anorectal disorders like proctitis. Fecal incontinence is the involuntary discharge of rectal contents and most often caused by neuromuscular disorders or structural anorectal problems. Diarrhea and urgency, especially if severe, may aggravate or cause incontinence. Many patients are hesitant to discuss it because of embarrassment.
However, it is important to ask about fecal incontinence because the condition requires
further evaluation. A careful history and physical examination generally allow these conditions to be discriminated from true diarrhea
• The duration of symptoms is important in the assessment of diarrhea. While infection is the leading cause of acute diarrhea (viral or bacterial), most cases of chronic diarrhea are noninfectious—IBS being the leading cause of chronic diarrhea
• History should include recent consumption of unsanitary food or water (raw or poorly cooked foods such as eggs, meat, shellfish, dairy products, fruits and vegetables, or foods that may have been improperly handled or stored). Patients should be asked specifically about the use of public swimming pools, recent travel (ETEC infection), antibiotic use within two months (PMC), domestic animal exposure (Campylobacter infection), previous surgery (cholecystec-tomy, intestinal resection and surgery for peptic ulcer disease), or radiation exposure
• A careful medication history should specifically screen for antibiotic use causing PMC, illicit drugs, alcohol, antacids, and laxative abuse. In chronic diarrhea, associated medical disorders such as diabetes mellitus, dysmotility diarrhea, arthropathies in IBD are helpful in the diagnosis
• Sexual history is important, particularly if there has been oral-genital or oral-anal contact. Homosexuals (gay bowel syndrome) and HIV individuals are at a higher risk for exposure to infectious agents, and diarrhea may be the initial presenting manifestation
• Past medical history should focus on any prior history of diarrheal illness, and significant underlying medical problems (e.g.
AIDS, diabetes, cirrhosis, sickle cell disease, cancer, endocrine - thyroid, Z-E syndrome, or autoimmune disease), prior radiotherapy, and immunological status.
Diarrhea 87
• Important features in the history which help guiding the evaluation and management of patients with acute diarrhea are:
Stool characteristics-frequency, consis-tency, quantity, bloody, mucus-filled, purulent, or greasy;
Presence of dysentery—fever, tenesmus, blood, mucus, or both;
Symptoms of dehydration—thirst, lethargy, postural giddiness, decreased urination; and
Presence of associated symptoms—
nausea, vomiting, abdominal cramps, and significant upper or lower gastro-intestinal bleeding (coffee ground emesis, hematemesis, melena, hematochezia).
• Some typical features of diarrhea and stools associated with common diseases are:
Nocturnal diarrhea—autonomic neuro-pathy, e.g. diabetes mellitus;
Diarrhea alternating with constipation -TB abdomen, laxative abuse, diverticu-losis, carcinoma of colon;
Chronic bloody or melanotic stools with weight loss - IBD, colonic malignancy;
Pale, bulky, greasy, frothy, foul-smelling stools, which float in toilet, and associated with nutritional deficiency, weight loss -malabsorption syndrome; and
Diarrhea worsened by eating fatty foods -steatorrhea.
• The Manning criteria (Table 13.1) are helpful to differentiate IBS from organic causes of diarrhea
• Table 13.2 illustrates common findings on physical examination and their significance in patients with diarrhea.
RED FLAGS
• Infection with E. coli O157: H7 presents with manyclinical manifestations and should be included in the differentialdiagnosis for any
patient with new-onset bloody diarrhea.
Development of the hemolytic uremic syndrome (HUS) or thrombotic thrombocy-topenic purpura (TTP) should raise strong suspicion of E. coli O157:H7 infectionand should lead to prompt evaluation
• Nocturnal diarrhea, unless occurring in a known diabetic patient, usually points to an organic cause
• Abdominal TB (intestinal or peritoneal) can mimic IBS and must be considered in chronic diarrheal disease, especially due to rising HIV incidence
Table 13.1: The Manning criteria to distinguish IBS from organic disease
1. Onset of pain associated with more frequent bowel movements
2. Onset of pain associated with looser bowel movements
3. Pain relieved by defecation 4. Visible abdominal bloating
5. Subjective sensation of incomplete evacuation more than 25% of the time
6. Mucorrhea more than 25% of the time Table 13.2: Physical signs in diarrhea
Physical signs Significance
General exam—Fever, Infection, IBD weight loss, tachycardia, Alcohol abuse, tremor, lymphadenopathy hyperthyroidism
TB, malignancy Skin — Erythema nodosum, IBD
dermatitis herpetiformis, Celiac sprue
flushing, Carcinoid syndrome
venous telangiectasis, Carcinoid syndrome hyperpigmentation Addison’s
disease,Peutz-Jeghers syndrome
Kaposi sarcoma AIDS
Punch’ purpura Amyloidosis
Eyes—Iritis,uveitis IBD
Neck—Goiter Hyperthyroidism
Lungs—Bronchospasm Carcinoid syndrome Abdomen—mass, Crohn’s disease
RLQ mass Colonic ischemia
Bruit
PR—Rectal fistula, Crohn’s disease painless fissure,
perianal abscess
88
• In general, a patient with any of the following warrants thorough work up:
Symptoms of dehydration: Particularly postural giddiness, diminished urine output, and excessive thirst;
Advanced age (> 70 years);
Clinically suspected neoplasm, carcinoid syndrome, colonic ischemia;
Compromised immune system; and
Inflammatory diarrhea: fever, blood and mucus in stools.
SELECTIVE GLOSSARY
Hemorrhagic colitis (E. coli O157:H7)— Entero-hemorrhagic E. coli (EHEC) strain designated E.
coli O157:H7 serotype, causing Hemorrhagic colitis, is a gram-negative rod-shaped bacterium, capable of producing potent toxins [verotoxic (VT), shiga-like toxin] that cause severe damage to the lining of the intestine. Undercooked or raw hamburger (ground beef) has been implicated in many of the documented outbreaks, however, E.
coli O157:H7 outbreaks have implicated alfalfa sprouts, unpasteurized fruit juices, milk, dry-cured salami, lettuce, game meat, and cheese curds. The illness is characte-rized by severe cramping abdominal pain, and diarrhea which is initially watery but becomes grossly bloody.
Occasionally vomiting occurs. Fever is either low-grade or absent. The illness is usually self-limited and lasts for an average of 8 days. The majority of infections resolve completely; some victims, particularly the very young, have developed HUS, characterized by renal failure and hemolytic anemia. In the elderly, it may be complicated by TTP with high mortality rate.
Because person-to-person transmission of E. coli O157:H7 isnot uncommon, and infection with this organism may cause severedisease, stool specimens from all patients with a history of acute bloody diarrhea should be cultured for E. coli O157:H7.
Melanosis coli—It is a pigmentation of the rectal and colonic mucosa due to use (or abuse) of anthraquinone type laxatives, and occurs because of the deposition of a brown black pigment called lipofuscin in the lamina propria of the colon. The initial event is mucosal cell death or apoptosis resulting from anthraqui-none laxative abuse. These cells are then phagocytosed by macrophages in lamina propria producing lipofuscin, which gives a dark color to the colonic mucosa. Its incidence is understandably higher in older population and people who suffer from conditions like IBS and chronic constipation, and is rising because of the popularity of the herbal remedies containing anthraquinone. Melanosis coli is a benign reversible condition with no malignant potential. The main importance of diagnosing Melanosis coli correctly lies in the fact that if it’s extensive, there may be difficulty in differentiating it from ischemic colitis. Withdrawal of the offending laxative, which nearly always can be substituted with a bulk laxative, is sufficient treatment.
Peutz-Jeghers Syndrome (Pronunciation: putz ja’gerz)—It is a hereditary disease caused by autosomal dominant mutations involving Chromosome 19. It is characterized by the presence of intestinal polyps, consistently in the jejunum, and mucocutaneous pigmentation with melanin spots (small, flat, brown or dark blue spots with an appearance of freckles) of the lips, buccal mucosa, and digits. Isolated melanotic mucocutaneous pigmentation without gastrointestinal polyps has also been described because of the genetic variability of the syndrome. History includes:
• Family history of Peutz-Jeghers syndrome
• Repeated bouts of abdominal pain in patients younger than 25 years
• Unexplained intestinal bleeding in a young patient
Diarrhea 89
• Prolapse of tissue from the rectum
• Menstrual irregularities in females (due to hyperestrogenism from sex cord tumors with annular tubules)
• Gynecomastia in males (possible due to the production of estrogens from Sertoli cell testicular tumors)
• Precocious puberty
• Gastrointestinal intussusception with bowel obstruction.
The risk of cancer remains elevated with disregard to the presence or the absence, as well as the number, of gastrointestinal polyps.
Pseudomembranous colitis—PMC is a descriptive term for colitides associated with pseudo-membrane formation (or plaques) on the colonic or small intestinal mucosa. Although small intestine can be involved in PMC, most cases encountered in the modern era involve only the colon. Clostridium difficile infection is responsible for virtually all cases of PMC; the basic mechanism in its pathogenesis being overgrowth of C. difficile and toxin production (toxin A is an enterotoxin, while toxin B is a cytotoxin) by the organism that causes a wide spectrum of illnesses, ranging from mild diarrhea to life-threatening PMC. The anaerobes that are normally present in the colon control colonization by C. difficile; therefore, antibiotics that are most active against anaerobic organisms are more commonly associated with PMC. Although clindamycin and lincomycin classically have been linked to PMC, virtually all antibiotics can cause PMC; its onset being within days after initiation of
antibiotic therapy, or can occur up to 6 weeks after discontinuation. Other causative factors for PMC are abdominal surgery, colonic obstruction, uremia, and prolonged hypotension causing hypoperfusion of the bowel. PMC also has been described with lymphoma, leukemias, and advanced HIV infection. Diagnosis is primarily by the detection of C. difficile, or its toxins in stool by ELISA techniques, or direct culture of C. difficile from the stool. CT scanning of the abdomen can be helpful by revealing the presence of bowel wall edema (>4 mm) and inflammation, particularly in cases involving the right colon. Although these findings are nonspecific, imaging studies are helpful in patients with severe disease in detecting complications (e.g. toxic dilation, perforation).
REFERENCES
1. Achkar E. What is a practical approach to outpatient evaluation of diarrhea in a previously healthy, middle-age patient? Cleve Clin J Med 2001;68:104.
2. Talley NJ, et al. Self-reported diarrhea: What does it mean?Am J Gastroenterol 1994;89(8):1160-4.
[PMID: 8053428: Abstract].
3. Fernández-Bañares F, et al. Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics. Am J Gastroenterol 2007 Nov; 102(11):2520-8. Epub 2006. [PMID:
17680846 : Abstract].
4. Bertomeu A, et al. Chronic diarrhea with normal stool and colonic examinations: organic or functional? J Clin Gastroenterol. 1991;13(5):531-6. [PMID: 1744388: Abstract].
5. Fine KD, et al. AGA Technical Review on the Evaluation and Management of Chronic Diarrhea.
Gastroenterology 1999;116:1464–86.
SYNOPSIS
Dyspepsia has been said to be ill-defined, poorly defined,defying definition, and vague and misunderstood.1,2 The Rome III committee recommends the following pragmatic definition of dyspepsia: “dyspepsia is defined as the presence of one or more dyspepsia symptoms that is considered to originate from the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms”.3,4
It further states that the term functional dyspepsia should preferably be replaced by more distinctively defined disorders: (1) meal-induced dyspeptic symptoms (postprandial distress syndrome), and (2) epigastric pain syndrome. However, the committee recommends this definition particularly for research purposes.5,6
A working definition of dyspepsia may be considered as episodic or persistent upper abdominal symptoms believed to arise from the upper digestive tract (i.e. epigastrium; pain in the right or left hypochondrium is not considered to constitute dyspepsia), which may or may not be related to eating, and may include epigastric pain, bloating, fullness, belching,
nausea or early satiety. Patients use this term variously to express a feeling of bloating, burping, heartburn (pyrosis), regurgitation, early satiety, acidity, and indigestion or ‘upset stomach’. It is often accompanied by anorexia, nausea, vomiting, or flatulence. Although these symptoms are imprecise and nonspecific, care in taking the clinical history will often facilitate making a tentative diagnosis and limit unnecessary investigations.7
The main concern of the physician is to allay patient’s fear of organic GI disease by standard work up, and emphasize ‘patient empowerment’, i.e. discuss and agree with the patient how best he/she can control their symptoms with treatments available, and advise when symptoms need further investigations to rule out a more serious underlying cause.
DIFFERENTIAL DIAGNOSIS Common
• Indiscriminate eating behavior* (too much, too rich, too fast).
* A rare cause of indiscriminate eating (hyperoral) behavior is frontotemporal dementia – vide infra ↓↓.
Dyspepsia
14
CHAPTER
91
• Functional dyspepsia (Nonulcer dyspepsia, i.e. NUD†, aerophagy, IBS)
• Peptic ulcer disease (PUD‡ e.g. duodenal ulcer, gastric ulcer, stress ulcer)
• GERD
• Medications (NSAIDs, iron supplements, oral antibiotics, corticosteroids, theo-phylline, digitalis, potassium chloride, bisphosphonates, metformin, acarbose, OTC agents/herbal-garlic, gingko, Saw palmetto)
• Substance use/abuse—(alcohol, tobacco, caffeine)
• Systemic disease—(IHD, viral hepatitis A infection, tuberculosis, sepsis)
• Parasites (intestinal amoebiasis, giardiasis, strongyloides)
• Psychogenic (anxiety, depression, somatization)
• Pregnancy.
Occasional
• Coronary ischemia
• Gastroparesis (diabetes mellitus, vagotomy)
• Hepatobiliary disease (cholecystitis, choleli thiasis)
• Pancreatitis (chronic)
• Organ failure (cardiac, renal, hepatic)
• Upper GI malignancy (esophagus, gastric).
Rare
• Ischemic bowel disease
• Hepatobiliary neoplasms (primary, secondaries).
• Pancreatic malignancy
• Intra-abdominal malignancy
• Gastrinoma (Zollinger-Ellison syndrome, i.e.
ZES: vide infra ↓↓)
• Metabolic (hypercalcemia)
• Carbohydrate malabsorption (lactose, fructose).
INVESTIGATIONS—GENERAL CBC
• Leukocytosis with infection (cholecystitis, pancreatitis, MI)
• IDA due to chronic GI bleeding
• Megaloblastic anemia in malabsorption and gastric carcinoma.
ESR
• Elevated in infection, malignancy.
FOBT and Parasites
• To screen for GI carcinoma, adenoma, intestinal ischemia, and IBD
• Stool microscopy/ ELISA for parasites.
ECG
• If coronary ischemia is likely.
Metabolic Panel
• Electrolytes, urea, creatinine, glucose, and calcium.
TFTs
• Performed to evaluate for hypothyroidism or hyperthyroidism.
LFTs, Amylase, Lipase
• Performed to check for pancreatic or obstructive biliary disease.
† The older synonym nonulcer dyspepsia, though still widely used, is not recommended because some of the patients have symptoms typical of ulcer disease while others have symptoms not at all like an ulcer. Furthermore, peptic ulcer is not the only organic disease to be excluded before the diagnosis of functional dyspepsia is appropriate. (Ref.
- Dyspepsia-A National Clinical Guidelines, Scottish Intercollegiate Guidelines Network; March 2003).
‡ PUD includes ulcer in the stomach, pylorus, duodenum, or a Meckel’s diverticulum, as well as ulcers at sites of GI anastomosis (stomal ulcer) and at the gastroesophageal junction.
Diagnosis: A Symptom-based Approach in Internal Medicine 92
INVESTIGATIONS—SPECIFIC
EGD with or without Biopsy for H. Pylori (HP)
• Endoscopy is indicated in:
All patients with dyspepsia aged >45 years;
In younger patients with positive HP serology, or urea breath test (UBT);
Presence of any ‘alarm ‘ features (see ‘red flags’ below);
History of ulcerogenic medications; and
To obtain biopsy (Bx) specimens, particu-larly of gastric ulcer.
Tests for HP
• These can be either noninvasive (serology, UBT, or stool antigen test), or invasive (histology, and rapid urease test)
• IgG serology is easy and most suitable for initial diagnosis of HP infection because of its easy availability and low cost; but a positive test only indicates an ongoing or previous exposure to HP, and not active infection. Therefore, this test is not useful for confirming eradication of the organism, and documenting successful treatment
• With the UBT, if HP is present, the urease produced by the organism breaks down ingested carbon 14 labelled (14C) urea into ammonia and labeled carbon dioxide, which can be detected in the patient’s breath. UBTs are useful both for diagnosing active infection and confirming eradication following treatment with antibiotics, because once HP is eradicated, urease is no longer produced.
The UBT is more sensitive and specific than serology testing, but its disadvantage is that it requires 14C (or 13C) detection equipment and tends to be more expensive
• Stool antigen test (PCR for HP), like UBT, is useful both for diagnosing active infection
and confirming eradication following therapy. It is inexpensive and the test of choice, especially in children
• Histology: Mucosal biopsies (four—two antral, and two corpus) obtained during endoscopy can be stained (H&E, Giemsa, or Genta stains) to identify HP
• In rapid urease test, the tissue specimen (obtained at the time of endoscopy) is placed in urea rich agar medium with a pH sensitive dye. A color change represents a positive test
• Culture of HP is not often considered as diagnostic tool due to the difficulty in culturing this fastidious organism; it is mostly confined to research laboratories
• Urine and saliva tests for HP have not yet been completely validated.
US Abdomen or CT
• Used as indicated to identify lesions that may be responsible for dyspeptic symptoms.
• Gallstones detected are usually not causative of dyspepsia.
Esophagography and Upper GI Barium Meal Series
• Indicated if endoscopy is difficult or impossible as in patients with altered esophagogastric anatomy. A good barium meal study will identify motility disorders of the esophagus, (esophageal dilatation, loss of esophageal peristalsis, poor esophageal emptying, and
‘birds beak’ tapering of the distal esophagus), which may be missed endoscopically.
Esophageal Manometry
• Not routinely used for mild to moderate symptoms because findings seldom influence further medical management; may be essential for patients who are undergoing surgery for GERD.
Dyspepsia 93
24-hour Esophageal pH Manometry
• Performed in patients who have unex-plained chest pain that does not respond to medications.
Fasting Serum Gastrin
• In patients with gastrin secreting multiple neuroendocrine tumors (MNE: vide infra↓↓) such as Zollinger-Ellison syndrome.
CLINICAL NOTES
• Dyspepsia for which an underlying disease process is thought to be responsible for the symptoms is described as organic dyspepsia, e.g.
PUD, esophagitis; when symptoms persist for more than 12 weeks, and for which no cause (structural or biochemical) can be found after investigation, is usually termed as functional dyspepsia—this entity is synonymously termed as NUD. The Rome III criteria for functional dyspepsia are stated in Table 14.1.
However, according to the Rome III criteria, frequent clinical overlap of functional dyspepsia with IBS and GERD is very common; but this overlap does not exclude a diagnosis of functional dyspepsia.8-11
Table 14.1: The Rome III diagnostic criteria for Functional dyspepsia
At least 3 months (which need not be consecutive), with onset at least 6 months previously, of 1 or more of the following:
• Bothersome postprandial fullness
• Early satiation
• Epigastric pain
• Epigastric burning
• No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms.
• The investigation of choice to make the diagnosis of NUD (functional) is endoscopy ofthe upper GI tract. As such NUDcan be referred to as investigated dyspepsia, which should bedistinguished from uninvestigated dyspepsia.12
• Categorizing NUD in the diagnostic subgroups such as ulcer-like, reflux-like, dysmotility-like, and nonspecific dyspepsia have not shown to be helpful in predicting diagnosis or response to treatment. This is mainly due to large amount of overlap between types of dyspeptic symptoms for patients with underlying gastric ulcer, duodenal ulcer, GERD, or NUD, which makes the clinical history of little use in directing therapy toward a specific disease state.13,14 However, careful history is important to:
Elicit classical symptoms of specific disorders, e.g. PUD, cholecystitis, GERD;
Detect complicated ulcer disease, e.g. IDA due to chronic GI blood loss, vomiting due to gastric or duodenal outlet obstruction, sudden, severe abdominal pain due to peptic perforation;
Elicit alarm symptoms (see below) that suggest a high probability of organic disease, and need further testing rather than empiric therapy; and
Detect atypical symptoms more sugges-tive of other disorders, e.g. MI, IBS.
• History should also include a complete review of medications and OTC agents (see above);
dosage reduction or discontinuation of the offending agent may relieve patient’s symptoms and avoid further expensive work-up
• Patient’s habits (alcohol, smoking), lifestyle, past
• Patient’s habits (alcohol, smoking), lifestyle, past