diarrhoea5

Antimotility agents are not indicated for infectious diarrhea, except for refractory cases of Cryptosporidium infection. Antimicrobial therapy is indicated for some nonviral diarrhea because most is self-limiting and does not require therapy.


Therapies recommended for some nonviral diarrheas include the following:

• Aeromonas species: Use cefixime and most third-generation and fourth-generation cephalosporins.
• Campylobacter species: Erythromycin shortens illness duration and shedding.
• C difficile: Discontinue potential causative antibiotics. If antibiotics cannot be stopped or this does not result in resolution, use oral metronidazole or vancomycin. Vancomycin is reserved for the child who is seriously ill.
• C perfringens: Do not treat with antibiotics.
• Cryptosporidium parvum: Administer paromomycin; however, effectiveness is not proven. Nitazoxanide, a newer anthelmintic, is effective against C parvum.
• Entamoeba histolytica: Metronidazole followed by iodoquinol or paromomycin is administered in symptomatic patients. Asymptomatic carriers in nonendemic areas should receive iodoquinol or paromomycin.
• E coli: Trimethoprim-sulfamethoxazole (TMP-SMX) should be administered if moderate or severe diarrhea is noted; antibiotic treatment may increase likelihood of hemolytic-uremic syndrome (HUS). Parenteral second-generation or third-generation cephalosporin is indicated for systemic complications.
• G lamblia: Metronidazole or nitazoxanide can be used.
• Plesiomonas species: Use TMP-SMX or any cephalosporin.
• Salmonella species: Treatment prolongs carrier state, is associated with relapse, and is not indicated for nontyphoid-uncomplicated diarrhea. Treat infants younger than 3 months and high-risk patients (eg, immunocompromised, sickle cell disease). TMP-SMX is first-line medication; however, resistance occurs. Use ceftriaxone and cefotaxime for invasive disease.
• Shigella species: Treatment shortens illness duration and shedding but does not prevent complications. TMP-SMX is first-line medication; however, resistance occurs. Cefixime, ceftriaxone, and cefotaxime are recommended for invasive disease.
• V cholerae: Treat infected individuals and contacts. Doxycycline is the first-line antibiotic, and erythromycin is second-line antibiotic.
• Yersinia species: TMP-SMX, cefixime, ceftriaxone, and cefotaxime are used. Treatment does not shorten disease duration; reserve for complicated cases.

diarrhoea4

The following may be noted in patients with diarrhea:

• stool pH level of 5.5 or less or presence of reducing substances indicates carbohydrate intolerance, which is usually secondary to viral illness and transient in nature.
• Enteroinvasive infections of the large bowel cause leukocytes, predominantly neutrophils, to be shed into stool. Absence of fecal leukocytes does not eliminate the possibility of enteroinvasive organisms. However, presence of fecal leukocytes eliminates consideration of enterotoxigenic E coli, Vibrio species, and viruses.
• Examine any exudates found in stool for leukocytes. Such exudates highly suggest colitis (80% positive predictive value). Colitis can be infectious, allergic, or part of inflammatory bowel disease (Crohn disease, ulcerative colitis).
• Always culture stool for Salmonella, Shigella, and Campylobacter organisms and Y enterocolitica in the presence of clinical signs of colitis or if fecal leucocytes are found.
• Look for C difficile in persons with episodes of diarrhea characterized by colitis and/or blood in the stools. Remember that acute-onset diarrheal episodes associated with C difficile may also occur without a history of antibiotic use.
• Bloody diarrhea with a history of ground beef ingestion must raise suspicion for enterohemorrhagic E coli. If E coli is found in the stool, determine if the type of E coli is O157:H7. This type of E coli is the most common, but not only, cause of HUS.
• History of raw seafood ingestion or foreign travel should prompt additional screening for Vibrio and Plesiomonas species.
  
  
  Other laboratory studies may include the following:
  

  • Serum albumin levels: Low in protein-losing enteropathies from enteroinvasive intestinal infections (eg, Salmonella spp, enteroinvasive E coli)
  • Fecal alpha1-antitrypsin levels: High in enteroinvasive intestinal infections
  • Anion gap to determine nature of the diarrhea (ie, osmolar vs secretory)
  • Intestinal biopsy: May be indicated in the presence of chronic or protracted diarrhea, as well as in cases in which a search for a cause is believed to be mandatory (eg, in patients with acquired immunodeficiency syndrome [AIDS] or patients who are otherwise severely immunocompromised)
    
     Because the pathogenesis of diarrhea can be either osmolar (due to the presence of an excess of unabsorbed substrates in the gut lumen) or secretory (due to active anion secretion from the enterocytes), the anion gap in the stools is occasionally used to ascertain the nature of the diarrhea. The stool anion gap is calculated according to the formula: 290 - [(Na+K) X 2]. If the value is more than 100, osmolar diarrhea can be assumed to be present. If the value is less than 100, the diarrhea has a secretory origin.

diarrhoea3

diarrhoea2

diarrhoea1

Treatment of autoimmune hepatitis

Symptomatic patients from the control arms of early treatment trials had mortality rates of approximately 50 percent at five years.  patients with serum aspartate aminotransferase levels at least 10 times ULN or more than 5 times ULN in conjunction with a 2 fold elevation in the gamma globulin level have mortality rates of 60 percent at six months. Finally, over 80 percent of patients with bridging necrosis or multilobular necrosis at presentation progress to cirrhosis and have a five-year mortality rate of approximately 45 percent.

 With regard to asymptomatic patients, some studies suggest that untreated patients have a lower survival rate than treated patients, whereas others suggest that survival is similar

 Referral to a hepatologist should be considered for patients who fail to go into remission with glucocorticoid therapy, who worsen despite therapy, or who have cirrhosis at the time of diagnosis. Patients presenting with fulminant hepatic failure should immediately be admitted to a hospital with liver transplantation capabilities whenever possible


 AASLD 2010 guidelines.  criteria:

• ALT or AST level greater than 10-fold the ULN
• Serum ALT, AST, or gamma globulin level greater than twice ULN if any of the following are present:

• Symptoms
• An elevated conjugated bilirubin or,  even if less than twice the ULN
• Interface hepatitis on biopsy

• Histologic features of bridging necrosis or multiacinar necrosis
• Cirrhosis with any degree of inflammation on biopsy
• Children with autoimmune hepatitis 

 Unclear indications for treatment — Treatment may not be required in asymptomatic patients with normal serum aminotransferase and gamma globulin levels who have minimal necroinflammatory activity on liver biopsy
However, it is reasonable to offer treatment to a patient with histologic evidence of interface hepatitis  particularly if the patient is younger (age less than 50 years) and is unlikely to have severe side effects related to therapy.

 We generally rebiopsy patients who are not receiving treatment to look for histologic evidence of disease progression after two years.

 No indication for treatment —  absence of inflammatory cells on liver biopsy and normal or near-normal serum aminotransferases. The diagnosis of autoimmune hepatitis may be presumed in such patients based upon the clinical setting, the presence of serologic markers of autoimmune hepatitis, and the absence of other causes of liver disease. Such patients may be at increased risk for the development of glucocorticoid-related side effects, and the benefit of treatment is uncertain. However, patients with cirrhosis and active inflammation may be candidates for treatment.
 

Special circumstances —

High risk of drug side effects — The risk of glucocorticoid-related side effects is increased in patients with brittle diabetes, osteoporosis, emotional lability or a history of psychosis, or poorly controlled hypertension. 

not necessarily contraindications but may influence the decision to use azathioprine or 6-mercatopurine or use a lower dose of prednisone. Budesonide may also be in option.

Cirrhosis —  treatment is generally not recommended for patients with cirrhosis and inactive disease. treatment should not be withheld for compensated or decompensated cirrhosis who have active disease. The response to treatment may be excellent, even those with bleeding varices or ascites. Many patients respond when treatment is initiated, and the 10-year survival for treated patients, including those with cirrhosis, exceeds 90 percent

Pregnancy — Women appropriately treated for autoimmune hepatitis can have successful pregnancies. Usual therapy consists of glucocorticoids and/or azathioprine, both of which appear to be safe during pregnancy, though azathioprine is listed as pregnancy class D. Cessation of therapy during pregnancy in such patients has been associated with relapse of the disease  

 -an increased risk of prematurity, low birth weight, and fetal loss 
-monitor during pregnancy and several months post-partum because of the risk of flares in disease activity 

 Children — Autoimmune hepatitis tends to be more severe in children compared with adults,

 Coexisting HCV — treatment should first be directed toward autoimmune hepatitis because of the danger of exacerbating autoimmune hepatitis with interferon-based therapy. Although this approach may result in increased viral levels of HCV, it is the safer initial strategy.

 EXPECTED RESPONSES TO TREATMENT AND PROGNOSIS — The goal of therapy is to achieve a sustained remission without the need for medications- 10 to 40 % of patients. Up to 90% of patients with moderate to severe autoimmune hepatitis will respond to treatment, with a decrease in serum transaminases along with symptom improvement within two weeks. Serum transaminases will fall into the normal range, after 12 or more months of treatment.
 incomplete response in 13 %of patients, and they worsen in 10 %(treatment failure)
 

Risk of treatment failure — :

• Those with established cirrhosis
• Those who develop disease at a younger age or have had a longer duration of disease before therapy
• Those who possess the HLA-B8 and/or HLA-DR3 phenotypes

 Chance of remission — Patients with normalization of their aminotransferase levels are more likely to achieve histologic remission (absence of interface hepatitis), though histologic remission lags behind biochemical remission by several months.  Approximately 65 and 80 percent of patients achieve remission by 18 months and three years, respectively (average of 18 to 24 months). The probability of remission decreases after two years.

Risk of relapse —  50 to 90 % of patients will relapse within 12 months of drug withdrawal. With retreatment, over 80 % of patients will again achieve remission. 13% of patients will achieve a sustained remission when drug withdrawal is again attempted, but the majority will require maintenance therapy.

  Patients who achieve histologic remission have a 20 to 30 percent chance of relapse once treatment is withdrawn, whereas those who have evidence of interface hepatitis have a 75 to 90 percent chance of relapse.

 Risk of cirrhosis — Patients who suffer from multiple relapses are at increased risk for cirrhosis compared with patients with a sustained remission after initial treatment (38 versus 4 percent). They are also at increased risk for death from liver failure or the need for liver transplantation (20 versus 0 percent).

  30 percent of adult patients and almost half of pediatric patients will have cirrhosis at the time of diagnosis and cirrhosis develops in another 30 to 50 percent of patients during follow-up. While 10-year survival is similar to that in patients with autoimmune hepatitis without cirrhosis, survival is lower after 10 to 20 years. Ultimately, 10 to 20 percent of patients will require liver transplantation.  5 percent of patients will develop hepatocellular carcinoma. patients who undergo transplantation, 20 to 30 percent will have a recurrence of autoimmune hepatitis.

 INITIAL THERAPY —  glucocorticoid with or without azathioprine. Patients with fulminant hepatitis and liver failure, will require liver transplantation.

 Fulminant hepatitis and acute liver failure — Patients with fulminant hepatitis and acute liver failure often require liver transplantation. trial of glucocorticoids (for two weeks or less) can then be given while performing the transplant evaluation and closely monitoring the patient's clinical status and Model for End-stage Liver Disease (MELD) score, reserving liver transplantation for patients who do not improve. Steroid in fulminant hepatitis-variable result.




limited data and clinical experience suggest that the two approaches have similar efficacy as initial therapy

 Azathioprine monotherapy is used for maintenance therapy but is not effective for induction therapy. For patients who cannot tolerate prednisone, combination therapy with azathioprine and budesonide may be an alternative

 The AASLD recommends glucocorticoid monotherapy or combination of a glucocorticoid and azathioprine. The BSG guidelines recommend glucocorticoid and azathioprine and do not recommend initial treatment with glucocorticoid monotherapy.

 Because azathioprine is a prodrug of 6-mercaptopurine and, on occasion, toxicity to azathioprine occurs to the prodrug only, we may substitute 6-mercaptopurine at one-half of the azathioprine dosage.

 azathioprine at a dose of 1 to 2 mg/kg daily is often used. Since azathioprine and 6-mercaptopurine have been associated with aplastic anemia in patients lacking TPMT enzyme activity, we obtain TPMT phenotyping prior to initiating therapy

 Serum transaminase, bilirubin, or gamma globulin levels are checked weekly during the taper. If the patient develops recurrent symptoms or worsening laboratory values during the taper, we maintain the patient at the lowest dose that controls symptoms

 When TPMT activity is low, there is an increase in 6-TG, which likely accounts for much of the drugs' toxicity. Measurement of metabolites can also be useful, particularly in patients who have not responded to treatment

 However, toxicity to azathioprine can occur independent of TPMT activity, and some patients intolerant of azathioprine can take 6-mercaptopurine without side effects. In addition, allopurinol, a xanthine oxidase inhibitor, can lead to the increased production of active metabolites and should generally be avoided

 For patients on combination therapy, monitoring includes [11]:

• Weekly liver tests, blood sugar, and blood cell count for four weeks and then every one to three months also including an IgG.
• Bone density testing at the beginning of glucocorticoid therapy and then every one to two years. 
• Screening for glaucoma and cataracts after one year on glucocorticoids.

Remission — defined by :

• Resolution of symptoms
• Normalization of serum aminotransferase levels
• Normalization of serum bilirubin and gamma globulin levels
• Improvement in liver histology to normal or only mild portal hepatitis (or minimal to no activity in patients with cirrhosis) 

- Arthralgias frequently persist despite remission
 -aminotransferase remain elevated in presence of coexisting non-alcoholic fatty liver disease. -gamma globulin levels remain elevated, may be secondary to other chronic inflammatory and/or autoimmune diseases.

 In patients receiving azathioprine for maintenance therapy, 6-thioquanine (6-TG) metabolite levels may predict the ability to maintain remission.  6-TG levels of >220 pmol/[8 x 10⁸ red blood cells] were more likely than those with lower average levels to have normal alanine aminotransferase levels (odds ratio 7.7)

 the presence of normal or near-normal serum aminotransferases does not necessarily indicate histologic normalization

 Withdrawing therapy — Once remission has been established, drug withdrawal can be attempted. The decision to use maintenance azathioprine or to wait for and treat the first relapse depends upon the estimated likelihood of relapse, severity of liver disease, and anticipated side effects. The British Society of Gastroenterology guidelines recommend routine maintenance therapy in younger patients and in patients who are LKM antibody or soluble liver antigen-positive.

 Treatment is generally continued long enough to permit histologic resolution. - at least two years, with normal aminotransferase levels for 18 months. While a liver biopsy may help predict successful drug withdrawal, it has not shown to affect long-term outcomes and not required prior withdraw therapy. However, our preference is to obtain a biopsy prior to withdrawing therapy and to continue treatment if there is significant interface hepatitis or other histologic evidence of active disease.

 We gradually taper the glucocorticoid over a six-week period in patients who achieve clinical remission. We monitor the serum transaminases, total bilirubin, and gamma globulin levels every three weeks during withdrawal and for three months after withdrawal. We then monitor the levels every six months for one year, and yearly thereafter.

 For azathioprine, we generally withdraw it after glucocorticoids have been discontinued. For patients taking 50 mg daily, we simply stop the azathioprine. For patients taking higher doses, we reduce the dose by 50 mg every three months with careful monitoring every three months. In some cases, azathioprine cannot be successfully withdrawn, and patients may need maintenance therapy.

Incomplete response to initial therapy — 13 percent of patients after 36 months 

• Some or no improvement in clinical, laboratory, and histologic features despite compliance with therapy for two to three years
• No worsening of the condition

require long-term maintenance therapy. These patients are managed similarly to those who relapse following remission.

Treatment failure — 10 percent 

• Sustained biochemical and histologic activity, leading to the development or worsening of cirrhosis with eventual complications and death.
• The need for orthotopic liver transplantation. 

 Wilson disease and the overlap syndrome of autoimmune hepatitis/primary sclerosing cholangitis (autoimmune sclerosing cholangitis) should be considered in young patients with treatment failure

 The optimal therapy of resistant disease is not well established. We generally administer azathioprine (2 mg/kg/day up to a maximum dose of 200 mg daily) or 6-mercaptopurine (1 mg/kg/day up to 100 mg daily), while increasing prednisone to 40 to 60 mg/day. In responding patients, we taper the dose of prednisone by 10 mg per month until conventional maintenance doses are reached (10 mg/day) or to the lowest dose associated with clinical improvement (minimum of 10 mg/day). We continue the azathioprine or 6-mercaptopurine for up to one year before considering a dose reduction. After one year of clinical improvement, we taper the dose of azathioprine by 50 mg each month until a dose of 50 mg/day is reached. For patients who enter remission with this regimen, we will consider withdrawing therapy. However, other patients may require long-term maintenance therapy.

 AASLD includes either monotherapy with prednisone (60 mg daily) or combination therapy with prednisone (30 mg daily) and azathioprine (150 mg daily). The regimen is continued for at least one month, after which the dose of prednisone is reduced by 10 mg and the dose of azathioprine reduced by 50 mg after each month of clinical improvement. Dose reduction is continued until conventional maintenance doses are reached.

 Cyclosporine, tacrolimus, budesonide, methotrexate, infliximab, and mycophenolate mofetil have also been used in small numbers of patients who fail or cannot tolerate conventional therapy. AASLD, has been to try mycophenolate mofetil (a total of 2 g daily orally)

 Finally, allopurinol has been tested in patients who are nonresponsive or intolerant to azathioprine or 6-mercaptopurine. When allopurinol is given in conjunction with a thiopurine, the metabolism of the thiopurine is shunted toward increased production of the metabolically active 6-thioguanine and decreased production of the toxic thiopurine metabolites. In a study of eight patients who received allopurinol in conjunction with a thiopurine, biochemical improvements were seen in all eight, with a sustained response in seven. However, if allopurinol (or other xanthine oxidase inhibitors) is used in conjunction with a thiopurine, it is important to monitor thiopurine metabolite levels

 Medication intolerance —  10 percent.
- treat with either glucocorticoids or azathioprine alone (whichever was tolerated) at a dose that controls disease activity.
If there is disease progression on the single agent, alternative therapies, such as mycophenolate mofetil can be considered.

 RELAPSE FOLLOWING SUCCESSFUL DRUG WITHDRAWAL — Relapse may be heralded by the development of fatigue, arthralgias, and anorexia accompanied by a rise in serum aminotransferase levels and/or an increase in serum gamma globulin levels. A rise in serum aminotransferases to more than three times normal or a rise in serum gamma globulins to more than 2 g/dL correlates strongly with the presence of histologic deterioration

 Treatment of relapses — to resume the drug therapy that initially leads to remission at induction doses. Once clinical remission, to withdraw the drug(s), since some patients will achieve a sustained remission despite multiple relapses

 Patients who continue to relapse can be treated with the lowest dose of either azathioprine or prednisone. Both strategies are effective in controlling the disease in the majority of patients. The decision to use azathioprine either as a steroid-sparing agent or as monotherapy involves weighing long-term steroid-induced side effects against those of azathioprine.
 
The following are reasonable approaches to making drug changes in patients taking azathioprine or prednisone for maintenance therapy:
In patients taking combination therapy in whom a prednisone alone strategy is desired, the prednisone dose is typically reduced first to the lowest level that maintains stability of the serum aminotransferases. The dose of prednisone can be decreased by 10 mg per week until a dose of 20 mg/day is reached. Tapering should then be by 5 mg increments per week until a dose of 10 mg/day is reached. At that point, tapering should be done in increments of 2.5 mg per week down to a dose of 5 mg daily. If laboratory tests worsen or symptoms return, the taper should stop and the previous dose resumed.
Azathioprine can then be discontinued by reducing the dose by 50 mg every three months with an increase in the dose of prednisone if needed. A typical maintenance dose of prednisone is less than 10 mg daily. Budesonide may have a role in this setting.

 In patients taking combination therapy in whom maintenance therapy with azathioprine alone is desired, the azathioprine dose can be increased to 2 mg/kg/day, and then the dose of prednisone can be decreased by 2.5 mg each month until complete withdrawal. If 6-mercaptopurine is chosen, the corresponding dose of 1 mg/kg/day is used.

 In patients taking prednisone alone in whom prednisone-free maintenance therapy with azathioprine alone is desired, azathioprine (2 mg/kg/day) or 6-mercaptopurine (1 mg/kg/day) can be added, after which the dose of prednisone can be reduced by 2.5 mg each month.

 Once on a stable dose of medication, we monitor the patient's serum aminotransferases, bilirubin, and gamma globulin levels every six months. In addition, we obtain repeat liver biopsies to assess for disease progression every two years or prior to withdrawing therapy

Partial suppression in frequent relapsers — refers to treating patients to alleviate symptoms and to maintain serum aminotransferase levels that are mildly to moderately elevated. Partial suppression can be achieved with low doses of prednisone, with or without azathioprine
Their long-term outcomes (mean follow-up four years) were similar to those seen in 31 patients receiving conventional treatment. Only 1 of the 22 patients entered sustained remission, while 16 continued therapy. Morbidity was less than in conventionally treated patients since steroid-induced side effects usually resolved with low-dose prednisone.

LIVER TRANSPLANTATION —

We refer patients for a transplantation evaluation if they have:

• Fulminant hepatitis and acute liver failure
• Decompensated cirrhosis with a MELD score ≥15
• Hepatocellular carcinoma meeting criteria for transplantation

 autoimmune hepatitis recurs in 20 to 30 percent of patients

AASLD indications for treatment —

• Immunosuppressive treatment can be considered in adults without symptoms and with mild laboratory and histological changes. The decision should be individualized and balanced against the risks of therapy. Referral of such patients to a hepatologist should be considered.
• Immunosuppressive treatment should not be instituted in patients with minimal or no disease activity or inactive cirrhosis, but such patients should be followed every three to six months.
• Immunosuppressive treatment should not be instituted in patients with serious preexisting comorbid conditions (vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension) or previous known intolerances to prednisone unless the disease is severe and progressive and adequate control measures for the comorbid conditions can be instituted.
• Azathioprine should not be started in patients with severe pretreatment cytopenia (white blood cell counts below 2.5 X 10⁹/L or platelet counts below 50 X 10⁹/L) or known complete deficiency of thiopurine methyltransferase (TPMT) activity. TPMT activity should be assessed prior to starting azathioprine in a patient with cytopenia.
• Immunosuppressive treatment should be instituted in children at diagnosis regardless of symptoms.