Steatorrhea

Etiology

The causes of steatorrhea are numerous and subclassified under three broad categories:

1. Conditions leading to exocrine pancreatic insufficiency (EPI)
2. Bile acid deficiency states
3. Diseases affecting the small intestine.

Most notable disorders in each category are given below[2][3][4][5][6][7][8][9][10][11]:

1. EPI due to chronic pancreatitis, cystic fibrosis (CF), and conditions resulting in pancreatic duct obstruction or resection of the pancreas (e.g., pancreatic tumors)
2. Bile acid deficiency either due to cholestasis e.g. primary biliary cirrhosis, currently referred to as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or inability to absorb bile acids in the distal ileum resulting in diminished bile acid pool e.g. ileal resection or Crohn disease of the ileum or deconjugation of bile acids e.g., small intestinal bacterial overgrowth (SIBO)
3. Diseases affecting proximal small intestines such as celiac disease, tropical sprue, giardiasis, Whipple disease, lymphoma, amyloidosis, SIBO, and HIV enteropathy

 Other rare causes of steatorrhea include lipase inhibitors such as orlistat, Zollinger-Ellison syndrome (increased production of gastric acid inactivates the pH-sensitive pancreatic lipases), and graft-versus-host disease.[3]

Epidemiology

In the early stages, steatorrhea may be unrecognized by many patients due to minimal or nonspecific presenting symptoms. Therefore, the exact prevalence and incidence of steatorrhea are challenging to estimate and often go underreported. Also, the epidemiology of steatorrhea depends on the epidemiology of various underlying causes, which is a topic of the discussion below.

In adults, chronic pancreatitis is the most common cause of EPI. Chronic pancreatitis has an annual incidence of approximately 4 per 100000 persons and a prevalence of about 42 per 100000 individuals in the U.S.[12] In children, CF accounts for most cases of EPI. CF is the most common lethal autosomal recessive condition affecting the White population.[13] The approximate prevalence of CF is 1 in 3000 births. About 85% of CF patients have pancreatic insufficiency.[13]

The prevalence of celiac disease is on the rise, and a recent study reported a global seroprevalence of 1.4%.[14] Also, there are differences in the prevalence depending on geographical location. Reports of a biopsy-proven celiac disease show lower prevalence rates in South America and Africa and higher rates in Europe and Oceania.[14] For example, in Europe, Germany has a lower prevalence of celiac disease, and the highest prevalence was in Sweden and Finland.[14] Celiac disease has a higher prevalence in certain high-risk groups such as type 1 diabetes mellitus, Down syndrome, Turner syndrome, IgA deficiency, William syndrome, and in first-degree relatives of celiac disease.[8][15]

Based on a study from the Netherlands, PBC had an incidence of 1.1 per 100000 (male to female ratio was 1 to 6.3), and the point prevalence was 13.2 per 100000 individuals in 2008.[16] Another study from the U.S. reported an overall incidence of PBC as 2.7 per 100000 person-years and age and sex-adjusted prevalence of 40 per 100000 with a similar female predilection.[17] PSC has a prevalence rate depending on the geographical location. A systematic review reported the incidence and prevalence rates of PSC ranging from 0 to 1.3 per 100000 people per year and 0 to 16 per 100000 people, respectively.[18] As there is no consensus on the definition of SIBO, its exact prevalence is unknown.[11]

Pathophysiology

EPI: Chronic exposure to alcohol is the most common etiological factor for chronic pancreatitis. The other notable risk factors for chronic pancreatitis include predisposing genetic mutations (PRSS-1, SPINK-1, CFTR, CTRC), autoimmune pancreatitis, pancreatic duct obstruction, and chronic nicotine exposure.[19] The exact pathophysiological pathways underlying chronic pancreatitis are unclear but may include mechanisms such as chronic ongoing parenchymal inflammation with acinar cell destruction, and ductal dysfunction, etc.[19] The histopathological changes include pancreatic atrophy with fibrous scarring, which may be focal or diffuse.[20]

CF is a multisystem disease as a result of mutations in the gene which encodes the CF transmembrane conductance regulator (CFTR).[13] In the pancreas, CFTR dysfunction results in thick viscous secretions along with defective bicarbonate flow resulting in EPI.

Cholestatic Diseases: The mechanisms underlying the development of chronic cholestatic liver diseases, including PBC and PSC, are not entirely understood. Both these disorders are characterized by portal inflammation and progressive fibrosis and eventually resulting in end-stage liver disease. Here, the reduction in bile flow results in the accumulation of toxic bile products, which leads to biliary epithelial damage.[21] This decrease in bile reaching the small bowel interferes with fat absorption and causes steatorrhea in these patients.

Celiac Disease: It is a chronic autoimmune-mediated enteropathy related to exposure to dietary gluten in genetically susceptible individuals. The genes which encode for major histocompatibility complex (MHC) class II proteins HLA-DQ2 and HLA-DQ8 are prerequisites for this disease. Ingestion of gluten (specifically the gliadin peptides from wheat, rye, and barley) by susceptible individuals, along with some unknown trigger factors, leads to pathogenesis.[8] Gliadin polypeptides are resistant to degradation in the gastrointestinal tract and can cross the small intestinal epithelial barrier. In the lamina propria, these peptides get deamidated by local extracellular tissue transglutaminase (TTG).[8] This deamidation increases the affinity of gliadin binding to the antigen-binding groove of HLA DQ2 or HLA DQ8 on antigen-presenting cells. Upon presentation to CD4+ T lymphocytes, the gliadin peptides trigger an immune response causing local inflammation, which results in the destruction of villi. In addition to adaptive immune dysfunction, patients with celiac disease also have defects in innate intestinal immunity. The histopathological changes include increased intraepithelial lymphocytes, intestinal villous atrophy (blunting or flattening of the villi), and crypt hyperplasia (elongation of the crypts).[22] These changes lead to the malabsorption of fats and fat-soluble vitamins.

SIBO: Under physiological conditions, several defense mechanisms regulate the microbiota in the gastrointestinal tract and prevent small intestine bacterial overgrowth. The significant factors in SIBO prevention include immunoglobin A, gastric acidity, bile, and defensins.[23] The aboral peristalsis with migratory motor complexes and an intact ileocaecal valve also play a vital role in preventing SIBO.[23] Any disturbances in these mechanisms could result in bacterial overgrowth.[23][11] Deconjugation of bile acids causes fat malabsorption along with other factors such as ongoing inflammation, increased intestinal permeability.[23][11]

History and Physical

Patients with steatorrhea present with bulky, pale, foul-smelling oily stools. These fatty stools tend to float in the toilet bowl and often challenging to flush as well. In the early stages, steatorrhea may be asymptomatic and go unnoticed. Patients also have other nonspecific manifestations of fat malabsorption such as chronic diarrhea, abdominal discomfort, bloating sensation, and weight loss. Children may present with growth failure and delayed puberty. In severe cases, loss of subcutaneous fat and muscle wasting may be evident. Manifestations of fat-soluble vitamin (A, D, E, and K) deficiencies can accompany fat malabsorption. Celiac patients can present with a variety of extraintestinal signs such as anemia, oral ulcers, and dermatitis herpetiformis rash. Abdominal pain is a predominant symptom in patients with chronic pancreatitis but also reported in other conditions such as SIBO, inflammatory bowel disease, and celiac disease. CF patients have sinopulmonary manifestations. Jaundice, fatigue, and pruritis are suggestive of cholestatic liver diseases such as PBC or PSC. Signs for end-stage liver disease such as splenomegaly, ascites can be noted in PBC or PSC.

Evaluation

The diagnosis of steatorrhea is based on clinical findings, laboratory tests, and radiological images. Endoscopy with small intestinal biopsy, liver biopsy, and other specialized investigations may be needed to detect the exact etiology of steatorrhea.

Quantitative estimation of fecal fat (exceeding 7 g per 24 hours) is an essential first step for the diagnosis of steatorrhea. The standard method of fecal fat quantification is by calculating the coefficient of fat absorption (CFA).[24] With a standard quantity of fat ingestion, CFA is the percentage of dietary fat that is absorbed.[24] Patients should follow a strict diet for five days containing 100 g of fats daily.[24] Stools are collected in the last 72-hour for fecal fat estimation. CFA over 92% is considered normal.[24] Even though accurate, this method is cumbersome and unpleasant for most patients. For evaluation of EPI, fecal elastase may be utilized instead of the 72-hour fecal fat testing. A value of more than 200 mcg/g of stool is considered normal; 100 to 200 mcg/g is indeterminate, and less than 100 mcg/g is abnormal and indicative of EPI. Here the advantage is the requirement of a single stool sample. However, in the early stages of EPI, this test has a lower sensitivity. Also, a formed stool is necessary for testing. Otherwise, the fecal elastase could be falsely low due to dilution.

For evaluation of chronic pancreatitis, a plain abdominal radiograph may show pancreatic calcification, abdominal CT or MRI scans may reveal calcifications of chronic pancreatitis and ductal dilatation, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) can offer a more detailed evaluation of pancreatic parenchymal and ductal changes in chronic pancreatitis.[25][26] Similarly, MRCP, ERCP, and endoscopic ultrasound (EUS) are indispensable in the evaluation of pancreatic tumors.

For evaluation of celiac disease, estimation of serum tissue transglutaminase IgA antibodies (TTG-IgA) with total serum IgA is the recommended screening test.[8] IgA endomysial antibodies (EMA-IgA) has the highest specificity and is an option if TTG-IgA is weakly positive.[8] In patients with IgA deficiency, both TTG-IgA and EMA-IgA may be falsely low. In this population, TTG-IgG and deamidated gliadin peptide IgG (DGP-IgG) are the recommendations for screening.[8] Patients with positive serological tests should be followed up with duodenal biopsies for confirmation.[8]

In patients suspected to have chronic liver disease, serum liver tests may reflect a cholestatic pattern, elevation of alkaline phosphatase and gamma-glutamyl transferase are frequent findings in both PBC and PSC. AST, ALT, and bilirubin may be normal or elevated. Anti-mitochondrial antibodies are noted in 90 to 95% of patients with PBC.[27] Liver biopsy is not routinely needed for the diagnosis of PBC. If done, a liver biopsy may show the destruction of interlobular bile ducts and cirrhotic changes in the later stages.

In PSC, magnetic resonance cholangiography (MRC) is the preferred modality and may show a multifocal narrowing of both intrahepatic and extrahepatic biliary ductal strictures. These strictures may be seen alternating with dilation, which is referred to as the "beaded" appearance.[28] ERCP or percutaneous transhepatic cholangiography is also helpful to delineate the biliary anatomy in PSC but not routinely utilized for the diagnosis due to their invasiveness.[28] In PSC, a liver biopsy is not a routine test, and when done, may demonstrate periductular fibrosis (onion skin fibrosis).[28] Even though specific, this finding is infrequent.[28] In PSC, a liver biopsy may be helpful in a few particular circumstances, such as for the evaluation of small duct PSC and also to exclude coexistent autoimmune hepatitis, which is referred to as overlap syndrome.[28] About 80% of patients with PSC have IBD. Due to this strong association, if previously undiagnosed, a workup for IBD is recommended at the time of diagnosis of PSC.

Endoscopy with direct aspiration and culture of the small intestinal contents was traditionally the gold standard test for SIBO.[11] However, due to its invasive nature and lack of consensus on the definition regarding SIBO, this method is less preferred.[11] Breath tests utilizing either glucose or lactulose are commonly used in clinical practice.[11]

Treatment / Management

Treatment of steatorrhea depends on the underlying conditions which cause steatorrhea.

• In patients with EPI, pancreatic enzyme replacement therapy (PERT) is the cornerstone of treatment.[29]
• Along with PERT, patients with EPI should receive normal to a high-fat diet and fat-soluble vitamin supplementation.[3] Fat restriction may improve the symptoms associated with steatorrhea but will worsen the nutritional status and is no longer a recommendation.
• In patients with SIBO, an empiric trial of antibiotics is recommended. In many institutions, rifaximin is preferable to other antibiotics such as ciprofloxacin, metronidazole, norfloxacin, doxycycline, and amoxicillin-clavulanic acid.[23][11]
• In patients with celiac disease, diet-centered recommendations include a strict life-long gluten-free diet, education about the disease, management of nutritional deficiencies, access to an advocacy group, and consultation with a skilled dietitian.[22]
• Ursodeoxycholic acid is the first-line treatment of choice for PBC.[30] About 40% of patients may not respond to ursodeoxycholic acid and may eventually need a liver transplant.[30]
• Even though ursodeoxycholic acid is often used in PSC, medical therapy is not effective in curtailing the disease progression. ERCP with stent dilatation is useful for symptomatic improvement in biliary ductal strictures in large intrahepatic or extrahepatic ducts.[28] Liver transplantation is the definitive treatment for PSC and, post-transplant recurrence is not uncommon.
(B3)

Differential Diagnosis

When assessing a patient with steatorrhea, the following conditions must be considered and ruled out:

• Alcoholic pancreatitis
• Hereditary pancreatitis (mutations in genes such as PRSS-1, SPINK-1, CFTR, CTRC)
• Pancreatic insufficiency due to inherited conditions such as CF, Shwachman-Diamond syndrome, Pearson marrow syndrome,  and Johanson–Blizzard syndrome
• Celiac disease
• Tropical sprue
• Chronic liver diseases such as PBC, PSC
• Advanced pancreatic cancer
• Distal ileal pathology (e.g., Crohn disease) or resection
• Giardiasis
• Whipple disease
• SIBO

 Following is the list of conditions that present with chronic diarrhea which can be mistaken for steatorrhea:

• Irritable bowel syndrome
• Carbohydrate malabsorption (e.g., lactose intolerance, fructose malabsorption)
• Chronic laxative abuse
• Chronic or recurrent gastrointestinal infections
• Withdrawal of opioids
• Endocrine causes (hyperthyroidism, Addisons disease, neuroendocrine tumors)

Prognosis

The prognosis of steatorrhea depends on the underlying etiology. Steatorrhea due to exocrine pancreatic insufficiency and disorders of the small intestine like celiac disease, tropical sprue, or giardiasis has a good prognosis. But steatorrhea due to  CF and bile salt deficiencies like in PSC and PBC has a poor prognosis because of the progressive nature of underlying etiologies.

Complications

Different causes of steatorrhea lead to different complications. Following are some complications that can occur due to steatorrhea:

• Weight loss in adults and other consequences of malnutrition such as increased susceptibility to infections, and increased morbidity and mortality from various disease states. Additionally, in children, malnutrition results in growth failure and poor neurological development
• Deficiencies of fat-soluble vitamins (A, D, E, and K)
• Poor bone health resulting in osteopenia, osteoporosis, and fractures (CF, celiac disease)
• Iron deficiency anemia, zinc deficiency (celiac disease)
• Dermatitis herpetiformis, non-Hodgkin lymphoma, adenocarcinoma of the upper gastrointestinal tract (celiac disease)
• Megaloblastic anemia due to B12 deficiency (in terminal ileum disease and SIBO)
• Pancreatic pseudocyst, ascites, splenic vein thrombosis, diabetes, pancreatic cancer (chronic pancreatitis)
• Seizure, osteopenia, ataxia, early bruising, headache, hyposplenism, and tetany (celiac disease)
• Cirrhosis, end-stage liver disease (PBC, PSC), malignancies such as cholangiocarcinoma, colon cancer in PSC