Steatorrhea, Chyluria, Gallstone (Cholelithiasis), Pancreatitis (Chronic and Acute) , Sprue (Celiac disease)

Disease, pathophysiology, symptoms/clinical presentation, diagnosis, treatment

1. Steatorrhea , Chyluria , Cholelithiasis , Pancreatitis and Sprue Akash Mahadev Iyer S 2 M.Sc Biochemistry University of Kerala Karyavattom Campus

2. MALABSORPTION  SYNDROME Group of disorders ( celiac disease, cystic fibrosis, Crohn's disease, chronic pancreatitis, Tropical sprue ) characterized by reduced intestinal absorption of dietary components and excessive loss of nutrients in the stool .

3. Tropical sprue -an acquired disorder (an enteropathic condition) that presents with chronic diarrhea, weight loss etc.. Etiology -often bacterial, viral , or parasitic infection or toxins in spoiled food Most common causes- intestinal infection with small intestinal protozoa including Giardia intestinalis , Cryptosporidium parvum , Isospora belli , Cyclospora cayetenensis and the microsporidia Epidemiology : Tropical sprue may occur after travelling to tropical areas such as the Caribbean, Southern India, Southeast Asia.

4. SYMPTOMS- Clinical features Villi of the small intestinal mucosa become blunted or obliterated. Diarrhea, steatorrhea , abdominal pain, weight loss, fatigue, Megaloblastic anemia ( Malabsorption of folate and vitamin B 12  deficiency ) , light colored stools, pallor. Sore tongue ( Vit B 12 deficiency ) ,Easy bruising ( Vit K deficiency ) Multiple nutritional deficiencies and anorexia Diagnosis Endoscopy Low levels of vitamins, hypoalbuminemia , prolonged PT Low levels of β -carotene Excess fat in feces The D xylose test & folic acid levels are abnormally low Macrocytic anemia Indirect pancreatic test (e.g., Pancreolauryl test -abnormal in as many as 64% cases due to reversible exocrine pancreatic insufficiency related to low pancreatic hormonal stimulation caused by the loss of enterocyte )

5. Treatment Broad spectrum antibiotics such as tetracycline and folic acid are the treatment of choice Rapid clinical response Recurrence is uncommon, especially if the patient is not a resident of or a frequent traveler to tropical areas Other antibiotics such as sulfonamides , Rifamixin is also used Diet for adults suffering from tropical sprue Cereals and cereal products Half fat milk, eggs, cheese fleshy fruits( Banana, papaya, mango, apple , Cane sugar Multivitamin tablets, curd, cooked rice Probiotic such as yoghurt with active cultures of Lactobacillus acidophilus , lactinex , bacid , to help re-colonize normal intestinal flora in people with antibiotic therapy Basic sanitation

6. Celiac disease Also known as celiac sprue , non tropical sprue , or gluten- sensitive enteropathy . Celiac disease can be defined as pathological intolerance of the intestinal mucosa to prolamines , which are storage proteins in cereal grains, that occurs in genetically predisposed individuals of all ages The disease is caused by a reaction to a protein (gluten) found in grain (wheat, barely, oats, and rye). Upon exposure to gluten, the immune system cross reacts, causing chronic inflammation and primary lesions of the intestinal mucosa. This disorder can result in the malabsorption of all nutrients as a result of the shortening or total loss of intestinal villi , which reduces the mucosal enzymes for nutrient digestion and the mucosal surface for absorption. Gluten comprises two different protein types, gliadins and glutelins Epidemiology Celiac sprue occurs in about 1 to 6 of 10,000 people in the Western world. The highest incidence is in western Ireland, where the prevalence is as high as 3 of 1,000 people Most prevalent chronic disease across Europe. More frequent in females (by about 2:1) than in males 

7. Prolamins  are a group of plant  storage proteins  having a high  proline  content and found on plant materials mainly like in the seeds of cereal grains:  wheat  ( gliadin ),  barley  ( hordein ),  rye  ( secalin ),  corn  ( zein ),  sorghum  ( kafirin ) and as a minor protein,  avenin  in  oats . They are characterised by a high  glutamine  and  proline  content and are generally soluble only in strong alcohol[70-80%] solutions,light acids,alkaline solution

8. Pathogenesis Celiac disease is polygenic and multifactorial , (it requires triggering by the environment in the form of gluten, HL antigens, DQ2 and DQ8 risk factors). These genes are expressed on the surface of B cells, T cells, and macrophages where they code for class ll MHC that has the function of presenting short peptide antigens to receptors on CD4+ (helper)T cells The histological damage -mediated by up-regulation of zonulin , a protein responsible for altering gut permeability. Tight junctions of intestine regulate passage of molecules of varying sizes In celiac disease , disruption of this controlled transit of larger molecules may allow antigenic peptide component of gluten to pass into the lamina propria ,- where they are recognized by inflammatory cells, containing DQ 2 or DQ8 genes- setting up an autoimmune reaction and resulting immune mediated damage.

9. Clinical presentation Profuse secretion of mucus interferes -absorption of nutrients and especially fat Diarrhea, Steatorrhea which occurs in about 50% of the patients, weight loss, growth failure Histology shows villous atrophy and crypt hyperplasia . Other symptoms Bloating, Gas , Indigestion, constipation Stools that float are foul smelling bloody or fatty Non intestinal symptoms Anemia Abnormal liver tests Osteoporosis, depression, fatigue, joint pain, mouth ulcers, unexplained weight loss, under nutrition Muscle weakness Epilepsy ,migraine A set of associated conditions with the celiac disease . The term associated condition refers to states that are found more frequently in patients affected by celiac disease. These conditions include genetic disorders such as Down syndrome, Turner syndrome and auto immune or neurological disorder

10. Diagnosis Small bowel biopsies- gold standard Serological test Celiac disease is characterized by the development of antibodies directed against the components of gliadin It is important that the patient not reduce or exclude gluten in diet before testing,as all tests may become negative Detection of IgA anti tissue glutaminase antibodies tTGA by ELISA - highly sensitive Anti gliadin - low sensitivity Treatment Gluten free diet- Clinical improvement- Mucosal damage recovery Multivitamins Gluten degrading enzymes enzyme supplement therapy Bacterial prolyl endopeptidases

11. Steatorrhoea Fatty diarrhoea resulting from malabsorption of dietary fat . Diarrhoea is characterized by pale, bulky, greasy foul-smelling stools that float ( because of increased air content and are difficult to flush away. Passage of stools that contain fat (>17 mmol or 6 g per day) and indicates fat malabsorption as a result of small bowel, pancreatic disease (pancreatic insufficiency resulting in lipase deficiency), or cholestatic liver/ biliary disease (resulting in intestinal bile salt deficiency)., celiac disease, bacterial overgrowth, CD, parasitic disease and Whipple disease. (25%) Weight loss medications such as orlistat and fat substitutes such as olestra can also be a causative.

12. Common symptoms include anorexia, bloating, flatulence. Fat malabsorption results in secondary nutrient deficiencies and systemic disease such as anemia, hypoalbuminemia , osteoporosis , cramps and paraesthesias . Occurs only after fat-containing meals and therefore not a daily symptom. As steatorrhea occurs after meals, it typically happens 2 to 3 times a day in individuals with a normal lipid-content diet. Weight loss and anorexia may also develop over time due to malnutrition. 2-6 g of ingested fat -normally excreted each day , -60 g may be lost in steatorrhea . Weight loss requires an increased energy intake High dietary protein and carbohydrates Fat soluble vitamins and minerals such as Ca Zn, Mg, and Fe should be supplemented Detection by Sudan staining

13. The following features should be inquired about in a patient's medical history. Prior surgical resection of the stomach, pancreas (e.g., Whipple operation, pancreatectomy ), gastrectomy ). Recurrent episodes of acute pancreatitis History of malabsorptive conditions (e.g., celiac disease, giardiasis , Whipple disease, HIV/AIDS, lymphoma, gastrointestinal amyloidosis ). Use of tetrahydrolipstatin ( orlistat ), meclofenamate sodium, or olestra (fat substitute used in cooking). Alcohol dependence (as it is a risk factor for cirrhosis and chronic pancreatitis). Diabetes, which can occur in chronic pancreatitis. Recurrent pulmonary/upper respiratory tract infections suggestive of cystic fibrosis gene mutations

14. Diagnosis Sudan stain of a random sample of homogenized stool Steatocrit is quantitative measure of fat as a proportion of a whole centrifuged homogenized stool sample.  [ 72-hour fat chemical analysis (van de Kamer method) is considered the most accurate test for fecal fat quantification, although a 24-hour sample is more commonly obtained. (time-consuming and infrequently performed properly by physicians). The following investigations can help determine whether it is only fat that is being malabsorbed , or other nutrients also.

15. Laboratory Fecal pancreatic elastase-1 -investigating pancreatic exocrine insufficiency -chronic pancreatitis Stool microscopy and culture for ova, cysts, and parasites when investigating possible infection with  Cryptosporidium,  Giardia , microsporidia ,  Cyclosporidium , or Clostridium difficile . Direct serum bilirubin , ALP, GGT tests IgA tissue transglutaminase titer, serum IgA level, and duodenal biopsy in a patient with suspected celiac disease (e.g., anemia, chronic diarrhea, distended abdomen, young age). Genetic mutation analysis, when considering inherited diseases of the pancreas, such as cystic fibrosis. Thyroid evaluation with TSH, free thyroid hormones, and thyroid radioiodine uptake scan ( scintigraphy ) to assess for hyperthyroidism. Imaging Abdominal CT scan with oral and IV contrast Ultrasound of the pancreas Magnetic resonance cholangiopancreatography (MRCP) Esophagogastroduodenoscopy (EGD) and small-bowel biopsy Colonoscopy

16. Chyluria Chyluria -fistulous communication between urinary and lymphatics . Chyluria , which is passage of chyle in urine that gives its milky appearance, Causes, - parasitic and nonparasitic . The lymph laden with fat -absorbed from intestine is responsible for the milky appearance. Large amount of chyle in urine can be easily identified on naked eye examination. Commonly encountered in the tropics and subtropics (filarial belt) ;uncommon in the western world. Though classified in to parasitic / non-parasitic causes the former predominate mainly due to filariasis

17. Clinical features Often asymptomatic ( monosymptomatic ) May be also polysymptomatic at times -existence of associated conditions such as dysuria , hematuria ,, backache, UTI, edema, hydroceles , hypoproteinemia ,, weight loss and malnutrition. Urological manifestation of lymphatic system disease which when prolonged may lead to nutritional deficiency, UTI, hematuria ( hematochyluria ) and a state of compensated immunosuppression . Prolonged massive chyluria -serious immunological and homeostasis deficits due to increasing IgG , and particularly IgA deficiency-  - State of depressed immunity ( lymphocytopenia ) with Opportunistic fungal infections and Promotion of malignant tumors (due to sup­pression of cellular immunity).

18. Diagnosis Confirmed by evaluating a sample of a postprandial urine for chylomicrons and triglycerides. Milky cloudy urine should be differentiated from phosphaturia (clears on adding 10% acetic acid), All patients should also be screened for filariasis with: Hb , TC and DC ( eosinophilia ), serum proteins, blood urea and serum creatinine , urine for acid-fast bacilli and UTI. Intravenous urography , retrograde pyelography and lymphangiography have been traditionally used to demonstrate abnormal lymphaticourinary fistulas

19. Cholelithiasis Gallstones are hardened deposits of the digestive fluid bile, that can form within the gallbladder. Vary in size and shape from as small as a grain of sand to as large as a golf ball. Gallstones occur when there is an imbalance in the chemical constituents of bile that result in precipitation of one or more of the components.

20. Composition of Gall stones Gallstones -composed mainly of cholesterol, bilirubin , and calcium salts, with smaller amounts of protein and other materials Three types of gallstones ( i ) Pure cholesterol stones-contain at least 90% cholesterol, (ii) pigment stones (brown or black)-contain at least 90% bilirubin Brown pigment stones are mainly composed of calcium bilirubinate and Black pigment stones contain bilirubin , calcium and/or tribasic phosphate Brown pigment stones  are soft and greasy, consisting of bilirubinate and fatty acids (Ca palmitate or stearate ). They form during infection, inflammation, and parasitic infestation (iii) mixed composition stones, which contain varying proportions of cholesterol, bilirubin and other substances such as CaCO ₃, Ca₃(PO₄)₂ and calcium palmitate

21. Cholesterol gallstone formation begins with the secretion of bile supersaturated with cholesterol from the liver. Initiated by nucleating factors such as mucin , microscopic crystals then precipitate in the gallbladder Excessive cholesterol biosynthesis, -main lithogenic mechanism in obese persons. In the non-obese , defective conversion of cholesterol to bile acids, due to a relatively low activity of cholesterol 7α hydroxylase , the rate limiting enzyme for bile acid biosynthesis and cholesterol elimination could result in excessive cholesterol secretion. Interruption of the enterohepatic circulation of bile acids could increase bile saturation. Pigment stones occur when RBCs are destroyed, leading to excessive bilirubin in the bile. Gallbladder sludge, i.e., Thickened gallbladder mucoprotein with tiny entrapped cholesterol crystals is thought to be the usual precursor of gallstones

22. Common symptoms of cholelithiasis Abdominal pain (typically localized to the right upper quadrant of the abdomen) Abdominal swelling, distension or bloating Abdominal tenderness Clay-colored stools Fever and chills Loss of appetite Nausea with or without vomiting Pain that radiates from the abdomen to the right shoulder or back Sweating Yellowing of the skin and whites of the eyes (jaundice). Prevalent in developed nations, but it is less prevalent in the developing populations that still consume traditional diets Its prevalence is especially high in the Scandinavian countries and Chile and among Native Americans. Gallstones are more common in North America, Europe, and Australia, and are less prevalent in Africa, India, China, Japan, Kashmir, and Egypt.[

23. Factors influencing gallstone disease Age, Gender, parity, and oral contraceptives Genetics Obesity and body fat distribution Rapid weight loss Diet Physical activity Drugs Diabetes

24.   Diagnosis of Gallstone Disease Diagnosed by history of recurrent episodes of right-upper-quadrant or epigastric pain, The three primary methods used to diagnose gallbladder disease are Ultrasonography , Nuclear scanning ( cholescintigraphy ), and Oral cholecystography . Treatment Open cholecystectomy was formerly the gold standard of treatment for gallstones, until the advent of laparoscopic cholecystectomy Chenodeoxycholic acid ( chenodiol ) and ursodeoxycholic acid ( ursodiol ) -dissolve gallstones, but chenodiol causes diarrhoea and abnormal aminotransferase levels, while ursodiol does not. Contact dissolution therapy of cholesterol gallstones -instilling solvents like the organic solvent methyl tert -butyl ether into the gallbladder through a percutaneous catheter placed through the liver. ( technically difficult and hazardous procedure ), Mixture of plant terpenes may also be useful for dissolving gallstones, when used in combination with a bile acid.

25. Pancreatitis Inflammation of the pancreas. Range in severity from-relatively mild, self limiting disorder to a rapidly fatal disease that does not respond to any treatment. Acute pancreatitis is commonly described as an autodigestion of the pancreas by the exocrine enzymes It produces, principally trypsin . 80% of patients with acute pancreatitis have biliary tract disease or a history of long-term alcohol abuse. Other less common causes of pancreatitis include bacterial or viral infection, with pancreatitis occasionally developing as a complication of mumps virus. Mortality is high because of shock, anoxia, hypotension, or fluid and electrolyte imbalances. Attacks of acute pancreatitis may result in complete recovery, may recur without permanent damage, or may progress to chronic pancreatitis.

26. Clinical Manifestations Severe abdominal pain is the major symptom. Pain in the mid epigastrium . Decreased peristalsis ; and vomiting that fails to relieve the pain or nausea. Pain is frequently acute in onset (24 to 48 hours after a heavy meal or alcohol ingestion); may be more severe after meals and unrelieved by antacids. Ecchymosis around the umbilicus, which may indicate severe hemorrhagic pancreatitis. Nausea and vomiting, fever, jaundice, mental confusion, agitation. Hypotension related to hypovolemia and shock. May develop tachycardia, cyanosis, cold, clammy skin. Respiratory distress and hypoxia. Myocardial depression, hypocalcemia , hyperglycemia, and disseminated intravascular coagulation (DIC).

27. Assessment and Diagnostic Findings Diagnosis- based on history of abdominal pain, the presence of known risk factors, physical examination findings, and diagnostic findings (increased urine amylase level WBC count; Hypocalcemia ; glucosuria and increased serum bilirubin levels in some patients. X-rays of abdomen and chest, ultrasound, and contrast-enhanced computed tomography (CT) scan. Hematocrit and hemoglobin levels are used to monitor the patient for bleeding. Serum amylase and lipase levels are most indicative (elevated within 24 hours; amylase returns to normal within 48 to 72 hours; lipase remains elevated for longer period). Gerontologic Considerations The mortality from acute pancreatitis increases with advancing age. Patterns of complications change with age ( eg , the incidence of multiple organ failure increases with age). Close monitoring of major organ function (lungs and kidneys) is essential, and aggressive treatment is necessary to reduce mortality in the elderly.

28. Care includes witholding food ( NPO-nil per os ) and drink and administering IV fluids (  IV dextrose 5% in water (D5W) ) and parenteral analgesia Bowel rest reduces pain Impaired microcirculation- major cause for pancreatic necrosis 80% of patients with acute pancreatitis, who are admitted to a hospital recover with a few days of IV fluids and bowel rest

29. Chronic pancreatitis Inflammatory disorder -progressive fibrosis leading to anatomic and functional destruction of the pancreas. Cells -replaced by fibrous tissue. The end result is obstruction of the pancreatic and common bile ducts and duodenum. Atrophy of the epithelium of the ducts, inflammation, and destruction of the secreting cells of the pancreas. Alcohol consumption in Western societies and malnutrition worldwide are the major causes . FREQUENCY OF INCIDENCE: among alcoholics is 50 times the rate in the Non drinking population.

30. Pathophysiology Long-term alcohol consumption causes hypersecretion of protein in pancreatic secretions, -protein plugs and calculi within the pancreatic ducts. Alcohol -toxic effect on the cells of the pancreas. Damage more severe in patients with diets low in protein and very high or very low in fat. Smoking heavy drinkers usually smoke . Fibrosis -common pathological characteristic feature -major risk factor for pancreatic cancer The major clinical characteristics of pancreatitis are abdominal pain localized to the upper-to-middle Abdomen, Abdominal distension, Nausea, Fever, Vomiting, Back pain, Jaundice, Hematemesis , Melena Diarrhea with foul-smelling, oily bowel movements and weight loss. Abdominal pain is the most common symptom found in 50% to 80% of cases, and it is the major cause for hospitalizations of patients related to pancreatitis. 

31. Clinical Manifestations • Recurring attacks of severe upper abdominal and back pain, accompanied by vomiting; opioids may not provide relief. Weight loss is a major problem. Altered digestion ( malabsorption ) of foods (proteins and fats) results in frequent, frothy, and foul- smelling stools with a high fat content ( steatorrhea ). •As disease progresses, calcification of the gland may occur and calcium stones may form within the ducts. Assessment and Diagnostic Methods Endoscopic retrograde cholangiopancreatography (ERCP) is the most useful study. Various imaging procedures, including magnetic resonance imaging (MRI), CT scans, and U ltrasound . A glucose tolerance test evaluates pancreatic islet cell function. Steatorrhea is best confirmed by laboratory analysis of fecal fat content.

32. Medical Management Preventing and managing acute attacks, relieving pain and discomfort, and managing exocrine and endocrine insufficiency of pancreatitis. Endoscopy -remove pancreatic duct stones, -manage pain and relieve obstruction. Pain and discomfort-analgesics; yoga -effective non pharmacologic method for pain reduction and for relief of other coexisting symptoms. Alcohol and foods that produce abdominal pain and discomfort. no other treatment will relieve pain if patient continues to consume alcohol. Diabetes mellitus resulting from dysfunction of pancreatic islet cells is treated with diet, insulin/ oral hypoglycemic agents. Pancreatic enzyme replacement therapy -for malabsorption and steatorrhea . Surgery to relieve abdominal pain and discomfort, restore drainage of pancreatic secretions,

33. Practical uroradiology : Chyluria Jia-Hwia Wang Celiac sprue . Farrell RJ, Kelly CP. Food science- Swaminathan , M. S. Nutrition Science - Srilakshmi B Bahr , Manson, and D. R. Bell. "Manson's Tropical Diseases.“ Chyluria - a clinical and diagnostic stepladder algorithmo I Igbal Singh, P Dargan , N Sharma Indian Journal of Nephrology World Journal of Gastroenterology- Celiac disease: From pathophysiology to treatment- Ilaria Parzanese et., al N utrition and Diagnosis -related care By Sylvia Escott -Stump Practical Gastroenterology and Hepatology Board Review Toolkitedited by Kenneth R. DeVault , Michael B. Wallace, Bashar A. Aqel , Keith D. Lindor Essentials of Rubin's Pathology edited by Emanuel Rubin, Howard M. Reisner Clinical Nutrition in Gastrointestinal Diseaseedited by Alan Buchman Celiac Disease Pathophysiology -Sonia S. Kupfer This Handbook for Brunner & Suddarth’s Textbook of Medical-Surgical Nursing Mechanisms of parenchymal injury and signaling pathways in ectatic ducts of chronic pancreatitis: implications for pancreatic carcinogenesis - Umesh K Bhanot REFERENCES