Crohn's disease - 2011 review

Crohn's disease is a chronic inflammatory condition affecting the GI tract at any point from the mouth to the rectum.

Symptoms and signs may consist of:

- diarrhea
- abdominal pain
- fever
- weight loss
- abdominal masses
- anemia

Extraintestinal manifestations of Crohn's disease include:

- osteoporosis
- inflammatory arthropathies
- scleritis
- nephrolithiasis
- cholelithiasis
- erythema nodosum

Laboratory findings

Acute phase reactants, such as CRP and ESR, are often increased with inflammation and may correlate with disease activity.

Levels of vitamin B12, folate, albumin, prealbumin, and vitamin D can help assess nutritional status.

Procedures often used to diagnose Crohn's disease:

- colonoscopy with ileoscopy
- capsule endoscopy
- computed tomography (CT) enterography
- small bowel follow-through

Diagnostic tools for extraintestinal manifestations or complications (e.g., abscess, perforation):

- ultrasonography
- computed axial tomography (CT)
- scintigraphy
- MRI

Medical management

Mesalamine products are used for mild to moderate colonic disease. Antibiotics (e.g., metronidazole, fluoroquinolones) are often used for treatment.

Patients with moderate to severe Crohn's disease are treated with:

- corticosteroids
- azathioprine
- 6-mercaptopurine
- anti-tumor necrosis factor agents (e.g., infliximab, adalimumab)

References

Diagnosis and management of Crohn's disease. Wilkins T, Jarvis K, Patel J. Am Fam Physician. 2011 Dec 15;84(12):1365-75.

Image source: Colon (anatomy), Wikipedia, public domain.

Cirrhosis - 2011 update from Am Fam Physician

Cirrhosis is the 12th leading cause of death in the United States. The mortality rate is 9.7 per 100,000 persons.

The most common causes of cirrhosis are:

- alcohol abuse
- viral hepatitis
- nonalcoholic fatty liver disease is emerging as an increasingly important cause

Patients with cirrhosis should be screened for hepatocellular carcinoma with imaging studies every 6-12 months.

Causes of hepatic encephalopathy include:

- constipation
- infection
- gastrointestinal bleeding
- some medications
- electrolyte imbalances
- noncompliance with medical therapy

Treatment

Lactulose and rifaximin are aimed at reducing serum ammonia levels.

Ascites should be treated initially with salt restriction and diuresis. Physicians should be vigilant for spontaneous bacterial peritonitis.

Patients with acute GI bleeding should be monitored in an intensive care unit, and should have endoscopy performed within 24 hours.

Prevention

Mechanisms to reduce the incidence of cirrhosis:

- treat alcohol abuse
- screen for viral hepatitis
- control risk factors for nonalcoholic fatty liver disease

Cirrhosis: Phil's story (video):



From NHSChoices: Many people enjoy a drink in the pub after work without realising how social drinking can damage health. Phil didn't realise the harm his alcohol intake was doing until he was diagnosed with cirrhosis of the liver. He talks about his experience and the shock he felt at being diagnosed.

References

Cirrhosis: diagnosis, management, and prevention. Starr SP, Raines D. Am Fam Physician. 2011 Dec 15;84(12):1353-9.

Cirrhosis - JAMA Patient Page, 2012.

Chronic Diarrhea - Diagnostic Evaluation

Chronic diarrhea is defined as a decrease in stool consistency (loose BM) for more than 4 weeks (Am Fam Physician, 2011).

It can be divided into 3 categories:

- watery
- fatty (malabsorption)
- inflammatory

Watery diarrhea

Watery diarrhea may be subdivided into:

- osmotic
- secretory
- functional, e.g. IBS

Watery diarrhea includes irritable bowel syndrome (IBS), which is the most common cause of functional diarrhea. Another example of watery diarrhea is microscopic colitis, which is a secretory diarrhea affecting older persons.

Laxative-induced diarrhea is often osmotic.

Malabsorptive diarrhea

Malabsorptive diarrhea is characterized by excess gas, steatorrhea, or weight loss. Giardiasis is a classic infectious example of malabsorptive diarrhea.

Celiac disease (gluten-sensitive enteropathy) is also malabsorptive, and typically results in weight loss and iron deficiency anemia.

Inflammatory diarrhea

Inflammatory diarrhea, such as ulcerative colitis (UC) or Crohn disease, is characterized by blood and pus in the stool and an elevated fecal calprotectin level.

Invasive bacteria and parasites also produce inflammation. Infections caused by Clostridium difficile (C. diff.) subsequent to antibiotic use have become increasingly common and virulent.


Image source: Escherichia coli, Wikipedia, public domain.

Not all chronic diarrhea is strictly watery, malabsorptive, or inflammatory, because some categories overlap.

References:

Evaluation of Chronic Diarrhea. Juckett G, Trivedi R. Am Fam Physician. 2011 Nov 15;84(10):1119-1126.
Skin patch vaccine to prevent travelers' diarrhea
Image source: Colon (anatomy), Wikipedia, public domain.

How to investigate mildly elevated liver transaminase levels

Mild elevations in the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST) are commonly found in asymptomatic patients.

The most common cause is nonalcoholic fatty liver disease (sometimes called nonalcoholic steatohepatitis or NASH), which can affect up to 30% of the U.S. population.

Other common liver causes include:

- alcoholic liver disease
- medication-associated liver injury
- viral hepatitis (hepatitis B and C)
- hemochromatosis



Pale stool and dark urine (click to enlarge the images). This is an example of "obstructive" jaundice with the classic constellation of tea-colored urine and clay-colored stool.

Less common liver causes include:

- alpha-1-antitrypsin deficiency (AAT)
- autoimmune hepatitis
- Wilson disease

Extrahepatic conditions can also cause elevated liver transaminase levels:

- thyroid disorders
- celiac disease
- hemolysis
- muscle disorders

Initial testing should include:

- fasting lipid profile (FLP)
- measurement of glucose
- serum iron and ferritin; total iron-binding capacity (TIBC)
- hepatitis B surface antigen and hepatitis C virus antibody

If above test results are normal, a trial of lifestyle modification is appropriate.

Additional testing may include:

- ultrasonography (USG) of liver
- alpha-1-antitrypsin (AAT) and ceruloplasmin
- serum protein electrophoresis (SPEP)
- antinuclear antibody (ANA), smooth muscle antibody (ASMA), and liver/kidney microsomal antibody type

GI evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for more than 6 months.

References:

Causes and evaluation of mildly elevated liver transaminase levels. Oh RC, Hustead TR. Am Fam Physician. 2011 Nov 1;84(9):1003-8.

Linaclotide for treatment of constipation - minimally absorbed peptide agonist of guanylate cyclase C receptor

Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. It consists of 14 amino acids. The sequence is:

H–Cys1–Cys2–Glu3–Tyr4–Cys5–Cys6–Asn7–Pro8–Ala9–Cys10–Thr11–Gly12–Cys13–Tyr14–OH

Two randomized, 12-week trials included 1,300 patients with chronic constipation (NEJM, 2011). Patients received either placebo or linaclotide once daily for 12 weeks.

The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in linaclotide groups.

Linaclotide reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks of linaclotide in chronic constipation.

References:

Two Randomized Trials of Linaclotide for Chronic Constipation. N Engl J Med 2011; 365:527-536August 11, 2011.

Image source: Colon (anatomy), Wikipedia, public domain.

Clinical Pearls in Gastroenterology from Mayo Clinic (video)

The social media department of Mayo Clinic combines journal articles and videos by the lead authors. This is a useful approach that should be followed by other journals, in addition to Mayo's own journal, Clinic Proceedings.



Dr. Amy Oxentenko, Assistant Professor of Medicine at Mayo Clinic, discusses "Clinical Pearls in Gastroenterology" (article abstract). Here is the 2009 edition of the same project.

References:

Clinical Pearls in Gastroenterology 2011. Amy S. Oxentenko, MD, John B. Bundrick, MD, and Scott C. Litin, MD

Quadruple therapy as first choice for eradication of H. pylori due to clarithromycin-resistance

Helicobacter pylori is associated with benign and malignant diseases of the upper gastrointestinal tract. Increasing antibiotic resistance has made alternative treatments necessary.

Diagnosis of Helicobacter pylori infection: 13C urea breath test or the stool antigen test as “test and treat strategy”. BMJ, 2012.

Empirical triple therapy (proton-pump inhibitor, clarithromycin, amoxicillin) is currently the first choice for eradication of Helicobacter pylori. As antibiotic resistance to clarithromycin (which has a crucial role in eradication) has increased. The eradication rate with triple therapy has gradually decreased below 80%, and even less.

The aim of this study reported in The Lancet was to assess the efficacy and safety of a new, single-capsule treatment versus the gold standard for H. pylori eradication (triple therapy).

A randomised, open-label trial of adults with H. pylori infection compared the efficacy and safety of:

- quadruple therapy: 10 days of quadruple therapy with omeprazole plus a single three-in-one capsule containing bismuth, metronidazole, and tetracycline

- standard therapy: 7 days of omeprazole, amoxicillin, and clarithromycin (editor note: why not 14 days of therapy?)

H. pylori eradication was established by negative 13C urea breath tests at 28 and 56 days after the end of treatment.

The eradication rates were 80% in the quadruple therapy group versus 55% in the standard therapy group.

The study authors concluded that quadruple therapy should be considered for first-line treatment in view of the rising prevalence of clarithromycin-resistant H. pylori. Quadruple therapy provides superior eradication with similar safety and tolerability to standard therapy.

References:

Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. The Lancet, Volume 377, Issue 9769, Pages 905 - 913, 12 March 2011.

Quadruple or triple therapy to eradicate H pylori. The Lancet, Volume 377, Issue 9769, Pages 877 - 878, 12 March 2011.

H. pylori eradication provides benefits to patients with functional dyspepsia http://goo.gl/UwxsT

H. pylori image courtesy of www.hpylori.com.au.

Hepatitis C: Teenager Jazzy's Story

NHS Choices: Teenager Jazzy was born with hepatitis C. This is her video diary about living with the condition.

Comments from Twitter:

@napernurse: Fortunate to live in UK where extensive med/psych prescriptions for HepatitisC covered by NHS. If liver transplant needed, that is covered too!

Porphyrias

From a Lancet review:

Hereditary porphyrias represent a group of 8 metabolic disorders of the haem biosynthesis. They are characterised by acute neurovisceral symptoms, skin lesions, or both.

Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors:

- 7 porphyrias are the result of a partial enzyme deficiency

- a gain of function mechanism is present in one new porphyria

Acute porphyrias present with acute attacks - severe abdominal pain, nausea, constipation, confusion, and seizure - and can be life-threatening.

Cutaneous porphyrias present with painful photosensitivity, skin fragility and blisters.

Porphyrias are still underdiagnosed. Screening of families to identify presymptomatic carriers and avoidance of precipitants is important.

References:

Porphyrias. The Lancet, Volume 375, Issue 9718, Pages 924 - 937, 13 March 2010.

Hepatitis delta virus

From a recent review in The Lancet:

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV). More than 15 million people are co-infected worldwide.

There are 8 genotypes of HDV. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid.

The nucleocapsid consists of:

- a single-stranded, circular RNA genome
- delta antigen, viral protein

HDV suppresses HBV replication but also causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation (liver failure).

The range of clinical presentation is wide, varying from mild disease to fulminant liver failure.

Treatment of HDV is with pegylated interferon alfa; however, response rates are poor.

Better understanding of the molecular structure of HDV may lead to new therapeutic targets for this most severe form of chronic viral hepatitis.

References:

Hepatitis delta virus. Sarah A Hughes MBBCh, Heiner Wedemeyer MD, Dr Phillip M Harrison MD. The Lancet, Volume 378, Issue 9785, Pages 73 - 85, 2 July 2011.

Mayo Clinic on procedure competency: "140 colonoscopies isn't cool. You know what's cool, 275 colonoscopies"

Mayo Clinic: GI professional organizations have traditionally recommended that gastroenterology (GI) fellows perform 140 colonoscopies before assessing competency. Robert E. Sedlack, M.D., of the Department of Gastroenterology and Hepatology at Mayo Clinic, discusses findings that suggest it takes an average of 275 procedures to acquire the skills needed to perform safe and effective exams.

The quote is from here:

"The Social Network" tells the story of how Facebook went from a college startup to essentially the only way that old friends keep in touch. Napster founder-turned-Facebook president Sean Parker gives site creator Mark Zuckerberg, some shrewd financial advice. "A million dollars isn't cool. You know what's cool? A billion dollars," he says.

Cirrhosis: Phil's story

From NHSChoices: Many people enjoy a drink in the pub after work without realising how social drinking can damage health. Phil didn't realise the harm his alcohol intake was doing until he was diagnosed with cirrhosis of the liver. He talks about his experience and the shock he felt at being diagnosed.

Related reading:

Cirrhosis - JAMA Patient Page, 2012.

Drug companies trying to "create" parasites for treating ulcerative colitis

Ulcerative colitis, a type of inflammatory bowel disease (IBD), is less common in countries endemic for helminth infections, suggesting that helminth colonization may have the potential to regulate intestinal inflammation in IBD. Therapeutic effects of experimental helminth infection have been reported.

According to a researcher: "What we found was that after worm infection, the regions of the colon that were previously not making mucus, were now making mucus again."

"That's a key factor in healing, and it looked like the mucus came back because the worms were causing the body to produce IL-22. This is a molecule that promotes epithelial growth and healing."

Studies suggest parasites can regulate the immune system in ways that prevent it from "going wild" and attacking healthy tissue, and possibly human evolution took that into account.

A case report in the journal Science Translational Medicine provides a cellular and molecular portrait of dynamic changes in the intestinal mucosa of an individual who infected himself with Trichuris trichiura to treat his symptoms of ulcerative colitis.

Tissue with active colitis had a prominent population of mucosal T helper (TH) cells that produced the inflammatory cytokine interleukin-17 (IL-17) but not IL-22, a cytokine involved in mucosal healing.

After helminth exposure, the disease went into remission, and IL-22–producing TH cells accumulated in the mucosa. Genes involved in carbohydrate and lipid metabolism were up-regulated in helminth-colonized tissue, whereas tissues with active colitis showed up-regulation of proinflammatory genes such as IL-17, IL-13RA2, and CHI3L1.

T. trichiura colonization of the intestine may reduce symptomatic colitis by promoting goblet cell hyperplasia and mucus production through TH2 cytokines and IL-22. Controlled helminth infections may lead to new therapies for inflammatory bowel diseases.

References:

Eat Your Worms: The Upside Of Parasites. NPR.

M. J. Broadhurst, J. M. Leung, V. Kashyap, J. M. McCune, U. Mahadevan, J. H. McKerrow, P. Loke, IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient. Sci. Transl. Med. 2, 60ra88 (2010).

Helminth Trichuris suis (pig whipworm) had no effect as therapy for allergic rhinitis

Ulcerative Colitis - NEJM update, 2011.

Image source: Trichuris egg in stool sample (40x). Wikipedia, GNU Free Documentation License, Version 1.2.

New hepatitis C treatment: 2 new medications may increase success rate to 70%

Mayo Clinic: Four million people in the U.S., 100 million worldwide, are infected with Hepatitis C. It's a virus you can get from blood transfusions given before 1990, shared needles, unclean tattoo needles and sometimes sex.

In many cases it leads to cirrhosis of the liver and eventually liver cancer. Standard treatment with interferon and ribavirin only cures about 45% of all patients. But thanks to two new medications, up to 70% of people with hepatitis C may be be cured. More than 40 medications are in development.

17% of U.S. hospitals now provide virtual colonoscopy

Medicare does not currently reimburse routine screening with virtual colonoscopy, but it does cover evaluations with "regular" colonoscopy.

References:

Virtual Colonoscopy Gains in Popularity. Is It Right for You? TIME.
Colonoscopy Developer Dies at 94 - NYTimes http://goo.gl/iBnOp - Dr. Wolff was unconventional and surely made headlines in his day.
When President Obama underwent his first-ever colon cancer screening last year, he chose virtual colonoscopy. USA Today.
Cleveland Clinic Colorectal Cancer Risk Assessment Tool. Get your score in 2 minutes (free).

Comments from Twitter:

@DrSilge (Robert Silge, MD): What are your thoughts? Inability to biopsy, extra radiation... I don't see benefit. W/ fam hist of Colon ca, I won't be signing up.

@DrVes: Correct, "physical" colonoscopy is the procedure of choice rather than the virtual one. In any case, the preparation is the toughest part and is the same for both procedures.

Chronic pancreatitis - The Lancet review

There are two forms of chronic pancreatitis

Chronic pancreatitis is a progressive fibroinflammatory disease that exists in 2 forms:

- large-duct forms (often with intraductal calculi)
- small-duct form

Causes of chronic pancreatitis

Chronic pancreatitis results from a complex mix of:

- environmental factors - alcohol, cigarettes, and occupational chemicals
- genetic factors - mutation in a trypsin-controlling gene or the cystic fibrosis transmembrane conductance regulator (CFTR)
- a few patients have hereditary or autoimmune disease

Management of pain

Pain is the main symptom that occurs in two forms:

- recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells)
- constant and disabling pain

Management of the pain is mainly empirical, involving:

- potent analgesics
- duct drainage by endoscopic or surgical means
- partial or total pancreatectomy
- steroids rapidly reduce symptoms in patients with autoimmune pancreatitis
- micronutrient therapy to correct electrophilic stress is emerging as a promising treatment

Steatorrhoea, diabetes, local complications, and psychosocial issues associated are additional therapeutic challenges.

References

Chronic pancreatitis. Dr Joan M Braganza DSc a , Stephen H Lee FRCR b, Rory F McCloy FRCS c, Prof Michael J McMahon FRCS d. The Lancet, Volume 377, Issue 9772, Pages 1184 - 1197, 2 April 2011.
Pancreatitis - JAMA Patient Page, 2012.

Image source: Wikipedia, public domain.

Aspirin 75 mg daily reduces incidence and mortality due to colorectal cancer

High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects (bleeding) might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. This study in The Lancet assessed the effects of aspirin on incidence and mortality due to colorectal cancer over 20 years.

In the four trials of aspirin versus control (mean duration of treatment 6 years), 2·8% of 14,000 patients had colorectal cancer during a follow-up of 18 years.

Aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, but not rectal cancer (0·90).

Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45), but not the distal colon (1·10). Benefit increased with duration of treatment - aspirin taken for 5 years or longer reduced risk of proximal colon cancer by 70% and also reduced risk of rectal cancer (0·58).

There was no increase in benefit at doses of aspirin greater than 75 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily.

Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.

References:
Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. The Lancet, Volume 376, Issue 9754, Pages 1741 - 1750, 20 November 2010.

Image source: Colon (anatomy), Wikipedia, public domain.

Barrett's esophagus - Mayo Clinic video

Mayo Clinic: Millions of people know what it's like to have to run for the antacids after a big pasta dinner. Most of the time heartburn is harmless, but people who suffer from chronic heartburn are at increased risk of a condition called Barrett's esophagus. And if you have it, your chances of getting esophageal cancer go up.

Doctors at Mayo Clinic studied whether or not burning away the Barrett's cells with heat from radiofrequency ablation gets rid of the problem. What they found was encouraging.

What's new in gastroenterology and hepatology from UpToDate

35% of UpToDate topics are updated every four months. The editors select a small number of the most important updates and share them via "What's new" page. I selected the brief excerpts below from What's new in gastroenterology and hepatology:

Hepatitis C virus (HCV) infection

Peginterferon alfa-2a was superior to peginterferon alfa-2b with regard to virologic response rates in patients with chronic hepatitis C virus infection, genotypes 1, 2, 3, or 4. Patients being treated for chronic hepatitis C virus infection should receive peginterferon alfa-2a rather than peginterferon alfa-2b.

72 weeks of therapy with peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 or 4 was not better than 48 weeks.

Chronic use of proton pump inhibitors (PPIs)

Chronic use of proton pump inhibitors (PPIs) may lead to an increased risk of fractures. FDA recommends that healthcare professionals who prescribe proton pump inhibitors should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.

Ulcerative colitis

Once daily dosing of delayed-release mesalamine (Asacol 400 mg tablets) 1.6 to 2.4 g/day was as effective as twice daily dosing for maintenance of clinical remission in patients with ulcerative colitis. Remission rates were 85% in both groups.

Crohn's disease

Capsule endoscopy was not a cost-effective third test for establishing the diagnosis of Crohn's disease after a negative ileocolonoscopy and either a CT enterography or small bowel follow-through x-ray.

Azathioprine in combination with infliximab or infliximab alone had a higher rate of glucocorticoid-free clinical remission than those treated with azathioprine alone. Combination therapy and infliximab monotherapy led to significantly more complete bowel healing than azathioprine alone.

Obscure gastrointestinal bleeding

Double balloon enteroscopy (DBE) detected bleeding sources in 78% of patients with obscure gastrointestinal bleeding. Small intestinal ulcers and erosions were the most common findings.

References:
What's new in gastroenterology and hepatology. UpToDate.

Statins Use in Presence of Elevated Liver Enzymes: What to Do?

The beneficial role of statins in primary and secondary prevention of coronary heart disease has resulted in their frequent use in clinical practice.

However, safety concerns, especially regarding hepatotoxicity, have driven multiple trials, which have demonstrated the low incidence of statin-related hepatic adverse effects. The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis, in which liver enzyme levels are elevated in the absence of proven hepatotoxicity.

"Ttransaminitis" is usually asymptomatic, reversible, and dose-related.


Lovastatin, a compound isolated from Aspergillus terreus, was the first statin to be marketed for lowering cholesterol. Image source: Wikipedia, public domain.

The increasing incidence of chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis C, has created a new challenge when initiating statin treatment. These diseases result in abnormally high liver biochemistry values, discouraging statin use.

A PubMed/MEDLINE search of the literature (1994-2008) was performed for this Mayo Clinic Proceedings review. The review supports the use of statin treatment in patients with high cardiovascular risk whose elevated aminotransferase levels have no clinical relevance or are attributable to known stable chronic liver conditions.

References:
Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Rossana M. Calderon, MD, Luigi X. Cubeddu, MD, Ronald B. Goldberg, MD and Eugene R. Schiff, MD. Mayo Clinic Proceedings April 2010 vol. 85 no. 4 349-356.