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11 Şubat 2017 Cumartesi

PBC - Primary biliary cirrhosis


The PBC diagnosis is based on 3 criteria;
  • Serum ALP increase, which is longer than six months and indicates cholestasis,
  • By indirect immunofluorescence method,> 1:40 AMA (+),
  • Histology of the liver compatible with the disease

If the other two criteria are compatible but AMA is negative, then AMA-negative PBC is mentioned. AMA is positive in 90-95% of patients.

Liver biopsy is necessary in the following situations.
  • When staging is required,
  • AMA (-) and / or ALP is normal.
  • If there is an increase in ALP levels and AMA is positive, the necessity of biopsy is controversial.

If the single biopsy finds that there are signs of different stages of the disease, the highest stage is considered.

Staging

Stage 1: Portal ducts predominantly have lymphocytic infiltrates. There are loss of septal and interlobular bile ducts (<100 μm) and non-caseating granulomas in the absence of sarcoidosis or tuberculosis.
Stage 2: Peripheral inflammatory infiltrate, cholangitis, granuloma, proliferation in ducts.
Stage 3: Septal or bridging necrosis, ducopenia (more than half of intralobular bile ducts disappeared) and copper depletion in periportal hepatocytes.
Stage 4: Severe cirrhosis

Non-caseating epithelioid granulomas are not present in other autoimmune diseases. The clinical significance is not yet known.

Clinical findings
The majority of patients (20-60%) are diagnosed before clinical manifestations occur. Interestingly, somehow, asymptomatic patients are older than symptomatic patients.

Fatigue is the most common symptom. The second common symptom is PRURITIS.

It is usually diffuse. Typically, itching worsens at night. Fabricated cotton also worsens the itch.

Itching often occurs in the first pregnancy and continues after birth.
Recent studies (2011) focus on the pruritic role of Lysophosphatidic acid (LPA), a potent neuronal inhibitor, in cholestasis.

Secondary metabolic bone disease can be seen in PBC. Bone density should be measured every 2 years and metabolic bone disease treatment (calcium, vitamin D) should be observed.

Dyslipidemia can be up to 85% in patients with PBC.

More than 50% of untreated patients develop portal hypertension during a 4-year follow-up period.

The risk of having HCC increased.

Total immunoglobulin level may be normal but IgM fraction may be elevated.

Unlike primary sclerosing cholangitis, PBC has no association with cholangiosarcoma.

70% of patients have another autoimmune disease at the same time.

Conditions such as keratoconjunctivitis sikka, reynaud phenomeni, limited cutaneous systemic sclerosis are more frequent.


Risk Factors for PBS
Female gender (10: 1)
PBS family history
The presence of non-PBS autoimmune disease
Pregnancy
Smoking history
Recurrence or recurrence of vaginal infection,
Tonsillectomy
Frequent use of hair dyes and nail dyes
Previous surgical history (such as appendectomy, uterine surgery)
Hepatitis A history
Contraceptive Pill use

Treatment
The only drug approved by the FDA in PBS treatment is Ursodeoxycholic acid (UDCA).

UDCA forms 4% of the bile acid pool and is more hydrophilic than other bile acids.

The most common side effect is diarrhea.

How does UDCA work?
It modifies the bile acid pool.

It reduces the level of proinflammatory cytokines.
UDCA reduces the degree of apoptosis and levels of vasoactive mediators.
The UDCA dose varies from 13-20 mg / kg as needed.

The use of immunosuppressive / immunomodulatory drugs (azothiopurine, cyclosporine, penicillamine, and colchicine) is not recommended if autoimmune hepatitis-PBC overlap is not present. If these drugs should be given in overlapping situations, they should be given in combination with UDCA.

Methotexsat can provide additional benefits in some subgroups of PBC when combined with UDCA.
Especially in early-stage patients, the long-term use of Corticosteroids and fibrates is not convincing.
Recent data suggest that B-cell depletion therapy may be helpful in PBC patients who are resistant to UDCA treatment.

Orthotropic liver transplantation

Prognosis

The most reliable predictor of prognosis in PBC is the serum bilirubin level.

Within 10 years after diagnosis, 26% of patients develop liver failure.

Median survival time after diagnosis in PBC is 9.3 years.


9 Şubat 2017 Perşembe

Metformin and renal impairment

At what stage should a patient with renal dysfunction stop medication using Metformin? To act too conservatively, does it mean to keep the patient away from the benefits of first-line medicine like metformin? What are the ideas of international diabetes associations in this regard? Or what are we going to give as an alternative?
​​In recent years, it has begun to be mentioned that cutt-off values ​​that have been used in America for a long time (serum creatinine> 1.5 mg / dL [> 133 mmol / L] or 1.4 mg / dL [124 mmol / L] are extremely limiting.
In the NICE guideline, in 2010, the cut-off value of creatinine determined for metformin was 150 μmol / L (1.7 mg / dL) or the calculated GFR was <30 mL / min / 1.73 m 2.
In the Canadian guideline published in the same year, it was suggested that if the calculated GFR <60 mL / min / 1.73 m 2, it should be used with caution and warnings, and should be cut if the calculated GFR <30 mL / min / 1.73 m 2.
In the same year, the Australian Diabetes Association recommends stopping the drug when the calculated GFR <30 mL / min / 1.73 m2. Careful use of metformin has been suggested when the calculated GFR is 45-60 mL / min / 1.73 m2 (3).
EMA (European Medicines Agency) has informed that about one year ago, considering the European-based considerations, the limits of renal function for metformin use could be relaxed a little more.
The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have briefly addressed this issue in 2015 (4).
In the article, if the calculated GFR is between 45-60 mL / min / 1.73 m2, it has been argued that the prescription of metformin is not contraindicated. Even in the same article, there are considerations for using metformin by careful follow up until the calculated GFR <30 mL / min / 1.73 m2.It is emphasized that DPP-4 inhibitors may be an option but dose adjustment should be considered (except for linagliptin) for renal insufficiency.
Eventually in August 2016, the FDA made a safety announcement for metformin. The FDA announced that metformin could be used for mild and moderate renal insufficiency in the light of accumulated data in the literature.

REFERANCES
1. National Institute for Health and Clinical Excellence.The Management of Type 2 Diabetes: 2010 NICE Guidelines [Internet]LondonU.K.National Institute for Health and Clinical Excellence2010Available fromhttp://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf. Accessed 21 October 2010


2. Canadian Diabetes AssociationClinical practice guidelines [Internet]2008Available fromhttp://www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed 5 December 2010

3. National evidence based guidelines for blood glucose control in type 2 diabetes. [Internet]. Available fromhttp://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/di19-diabetes-blood-glucose-control.pdf. Accessed 5 December 2010.


Metformin-renal foksiyonlar: Ne kadar korkalım!


Metformin kullanan hastaya bu ilacı bıraktırmak için böbrek fonksiyon bozukluğu ne aşamada olmalıdır? Fazla muhafazakar davranmak acaba hastayı metformin gibi birinci sıra olan bir ilacın faydalarından uzak tutmak manasına mı geliyor? Peki, uluslararası diyabet cemiyetlerinin bu konudaki fikirleri nedir? Ya da ne vereceğiz alternatif olarak?
Son yıllarda,  ABD’de uzun zamandır kullanılan cutt-off değerlerinin (Erkekte serum kreatinin >1,5 mg/dL [>133 mmol/L] veya kadında 1,4 mg/dL [124 mmol/L]), belki de fazlasıyla sınırlayıcı olduğundan bahsedilmeye başlanılmıştır.
NICE kılavuzunda, 2010 yılında, metformin için belirlenen renal cut-off değerlerinin 150 µmol/L (1.7 mg/dL) veya  hesaplanan GFR’nin < 30 mL/min /1.73 m2 olması durumunda ilacın kesilmesinin uygun olacağı görüşüne yer verilmiştir (1).
Aynı yıl yayınlanan kanada kılavuzunda ise,  hesaplanan GFR <60 mL/min / 1.73 m2 olduğunda gerekli dikkat verilerek ve uyarılarla kullanılmasını ve eğer hesaplanan GFR <30 mL/min / 1.73 m2 ise kesilmesini önermiştir (2).
Yine aynı yıl, Avustralya Diyabet Cemiyeti hesaplanan GFR <30 mL/min / 1.73 m2 olduğunda kesmeyi, ve 45-60 mL/min / 1.73 m2 olduğunda ise kontrollü kullanımı önermiştir (3).
EMA (Europan Medicine Agency), Avrupa kökenli değerlendirmeleri dikkate alarak yaklaşık 1 yıl önce metformin kullanımı için renal fonksiyonların biraz daha gevşetilebileceğini bildirmişti.
ADA (TheAmerican Diabetes Association) ve European Association for the Study of Diabetes (EASD) bu konuya 2015 yılında kısa da olsa değinmiş (4). Birçok hekimin hesaplanan GFR’nin 45-60 mL/dk/1,73 m2 olduğunda da metformin yazmaya pozitif baktığı ve hatta aynı yazıda hesaplanan GFR <30 mL/dk/1,73 m2 olana kadar yazılmasının çok sıkı takip yaparak mümkün olduğu düşüncelerine yer verilmiştir. Yazının devamında ise, DPP-4 inhibitörlerinin bir seçenek oluşturabileceği, ancak doz ayarlamasına dikkat edilmesi (linagliptin hariç) gerektiğine vurgu yapılmıştır.
Nihayetinde 2016 Ağustos ayında, FDA’da, metformin için bir güvenlik duyurusu yaptı. Metforminin laktik asidoz riski nedeniyle ABD’de yasak olduğu ve tüm dünyada kullanılırken ABD’nin 1994 yılına kadar buna izin vermediği tarihsel bilgisi göz önüne alınırsa, FDA’dan gelen bu açıklamanın zamanlamasının, diğer kuruluşlara göre yine biraz ihtiyatlı olduğu söylenebilir.


KAYNAKLAR

1. National Institute for Health and Clinical Excellence.The Management of Type 2 Diabetes: 2010 NICE Guidelines [Internet]. London, U.K., National Institute for Health and Clinical Excellence, 2010. Available fromhttp://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf. Accessed 21 October 2010
2. Canadian Diabetes Association. Clinical practice guidelines [Internet]. 2008. Available fromhttp://www.diabetes.ca/files/cpg2008/cpg-2008.pdf. Accessed 5 December 2010

3. National evidence based guidelines for blood glucose control in type 2 diabetes. [Internet]. Available fromhttp://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/di19-diabetes-blood-glucose-control.pdf. Accessed 5 December 2010.

4. Diabetes Care. 2015;38:140-149

8 Şubat 2017 Çarşamba

Exercise-induced hematuria

Exercise-induced hematuria is the appearance of gross or microscopic hematuria following an intense exercise, in the absence of apparent kidney or urinary tract disease, and the recovery of this hematuria with rest.
In sports such as football or kick-boxing, direct trauma to the kidney or bladder may be the cause of hematuria. In addition, there may be trauma to the bladder in long distance runs and cycling. The risk is greater in the empty bladder.
Hematuria can also develop in non-contact sports such as swimming and shovels. One of the possible mechanisms is the accumulation of blood in the muscles and the development of renal ischemia. Another possible mechanism is the development of lactic acidosis and increased glomerular permeability as a result of exercise. Thus, the erythrocytes pass urine.
Bir başka olası sebep ise nutcracker sendromudur. Bu sendrom, sol renal venin, aorta ile süperior mezenterik ven arasında sıkışması olarak bilinir. Hematüri sıklıkla asemptomatiktir, ancak sol flank ağrısıyla birlikte de olabilir.
Exercise-induced hematuria is known as a benign condition with no long-term morbidity related. Diagnosis is a diagnosis of exclusion.
If the hematuria that starts after the exercise does not end within 1 week, other diagnoses should be considered.
If erythrocytes are not dysmorphic, further research should be considered.
Hematuria associated with exercise, should be distinguished from myoglobinuria following exercise and marginal hemoglobinuria.
Exercise induced hematuria may also be present in patients with erythrocyte membrane spectrin abnormalities.

6 Şubat 2017 Pazartesi

EGZERSİZE BAĞLI HEMATÜRİ

Egzersize bağlı hematüri, görünürde böbrek ya da üriner sistem hastalığı olmaksızın ağır egzersizi takiben gros ya da mikroskobik hematüri görülmesi, istirahatle geri dönmesi olarak tanımlanabilir.
Futbol ya da kik-boks gibi sporlarda böbreğe veya mesaneye gelen direk travmalar hematüri nedeni olabilirler. Ek olarak, uzun mesafe koşularında ve bisiklette de mesaneye travma olabilir. Boşa yakın mesanede risk daha fazladır.
Yüzme, kürek gibi non-kontakt sporlarda da hematüri gelişebilir. Olası mekanizmalardan birisi kanın adalelere birikip renal iskemi gelişmesidir.  Diğer bir olası mekanizma da, egzersiz sonucu laktik asidoz gelişmesi ve glomerüler permeabiliteyi arttırmasıdır. Böylece eritrositler idrara geçer.
Bir başka olası sebep ise nutcracker sendromudur. Bu sendrom, sol renal venin aorta ve süperior mezenterik ven arasında sıkışması olarak bilinir. Hematüri sıklıkla asemptomatiktir, ancak sol flank ağrısıyla birlikte de olabilir.
Egzersize bağlı hematüri, uzun dönemde sıkıntı çıkarmayan benign bir durum olarak bilinmektedir. Tanı, dışlama tanısıdır.
Eğer egzersizi takiben başlayan hematüri 1 hafta içinde sonlanmıyorsa başka tanılar göz önüne gelmelidir.
Eğer eritrositler dismorfik değilse, yine ileri araştırma düşünülmelidir.
Egzersiz hematürisi, egzersizi takiben oluşan miyoglobinüri ve yürüyüş hemoglobinürisinden ayırt edilmelidir.
Egzersiz in tetiklediği hemoliz, eritrosit membran spektrinlerinde sorun olan hastalarda da olabilmektedir.
50 yaş üzeri insanlarda mesane kanseri veya böbrek kanseri göz önünde tutulmalıdır.


SERRATİA ENFEKSİYONLARI

Enterobakter grubuna ait, Gram-negatif basillerdir. En az 15 türü vardır. Cins, fakültatif anaerob gram-negatif çubuklardan oluşmaktadır. Kırmızı boyanır. Hastaneden kazanılmış olan suşlar genelde beyaz-kremsi boyanırlar ve standart inkübatörlerde iyi çoğalırlar (35-37C).
S.marcescens ve diğer Serratia türleri, çok fazla virülans faktörü salgılamazlar ve oportunistik olarak düşünülürler.  Hareketlidirler ve fimbriaları aracılığıyla hücrelere adhere olabilirler. S.marcescens, değişik hücre tiplerine toksik olan birkaç farklı hemolisin salgılayabilirler.
İnsandaki Serratia enfeksiyonları  daha ziyade ekzojen çevreden kaynaklanmaktadır. Hayvanlardan vs bulaşmaz. Genelde direkt olarak toprak, su vs ile temastan kazanılır. Serratia türleri sıklıkla hastane içi salgınlarla ilişkilendirilirler, hastane dışı salgınlar çok mutad değildir. Steril olması gereken hazır solüsyonlardan vs. fabrikasyon hatası olarak salgınlar tanımlanmıştır.
Bireysel hastane kökenli Serratia enfeksiyonu çok sık değildir. Hastada invazif bir cihaz varlığı hastaneden kazanılmış Serratia türleri için önemli bir risk faktörüdür. Ancak, surveyans verileri Serratia’nın cihaz ilişkili enfeksiyon patojeni olarak baskın karakterde olmadığını göstermektedir. Daha ziyade ortak kaynak salgınlarına yönelmek gerekir.
S.marcescens, üriner trakt enfeksiyonu, pnömoni ve kan akımı enfeksiyonu yapabildiği gösterilmiş bir insan patojenidir.  İntravenöz ilaç kullanılanlarda enfektif endokardit yapabilmektedir. Deri ve yumuşak doku enfeksiyonları, cerrahi alan enfeksiyonları hatta nekrotizan fasciit, osteomiyelit, septik artrit sık olmamakla birlikte tanımlanmıştır.
SSS enfeksiyonları genelde ventriküloperitoneal şant, lomber ponksiyon, veya spinal enjeksiyonlara bağlanmıştır. Yenidoğanlarda meningoensefalit bildirilmiştir.
Serratia türleri, gözü diğer bölgelere göre daha fazla tutar. P.aeruginosa’dan sonra hastane kaynaklı oküler enfeksiyonun en sık nedeni olarak bildiren çalışmalar vardır. Konjunktivit, keratokonjuktivit, korneal ülserler ve keratit şeklinde olabilir. Serratia kaynaklı endoftalmit seyrektir ama uzun dönem sonlanımı kötü olabilir.
Serratia türlerinde ampisilin, amoksisilin, ampisilin-sulbaktam, amoksisilin klavulanata doğal olarak direnç sahibidir. Aynı şekilde, dar spektrumlu sefalosporinlere (cefazolin gibi), cephamycin’e, makrolidlere, tetrasiklinlere ve nitrofurontain’e de dirençlidir. AmpC betalaktamaz üreterek geniş spektrumlu beta-laktam direnci de yapabilirler. ESBL üretimi ve karbapenemaz üretimi de tanımlanmıştır.
Serratia türleri florokinolonlar, aminoglikozidler, trimotoprim-sülfametaksazol, piperasilin-tazobaktam, tikarsilin-klavulanat, 3. Ve 4. Kuşak sefalosporinler, aztreonam ve karbapenemler gibi bir seri antibiyotiğe duyarlıdırlar.






5 Şubat 2017 Pazar

TREATMENT OF HYPERCALCEMIA

Patients with mild hypercalcemia (<12 mg / dL) have no indications for immediate treatment. It may be advisable to increase fluid intake to reduce the risk of nephrolithiasis.
Intermediate hypercalcemia (12-14 mg / dL) may not require immediate treatment. An acute rise in serum calcium can cause significant impairment in mental status and requires urgent treatment.

Severe hypercalcemia (> 14 mg / dL) should be treated;
The isotonic saline should be given at a rate of 200-300 mL / h and a rate of 100-150 mL / h urine output. If there is no heart / kidney failure, it is not necessary to give loop diuretics.

Calcitonin (4 IU / kg) should be given and serum calcium measured after hours. If hypocalcemic response is observed, this can be repeated every 6 to 12 hours (4-8 IU / kg).
Zolendronic acid (4 mg i.v., over a 15 minute period) should be started concurrently with treatment. The other alternative is pamidronate.
Administration of saline with calcitonin will cause a reduction in calcium in 12 to 48 hours. The bisphosphonate reduces serum calcium within 2 to 4 days.
Donesumab is an alternative drug in a patient with malignant, Zolendronic acid-resistant, severe hypercalcemia.
Hemodialysis.
The most common cause of hypercalcemia in non-hospitalized patients is HYPERPARATHYROIDISM.

Hydration with isotonic NaCl

Hypovolemia causes hypercalcemia by impairing renal clearance of calcium.
With saline treatment, hypercalcemia on a moderate level often does not become normal. Simultaneous bisphosphonates should also be initiated. If necessary calcitonin can be started.

Calcitonin

At pharmacological doses, calcitonin acts by increasing renal calcium excretion and, more importantly, by impairing osteoclast function and reducing bone resorption. Nasal form is not successful in hypercalcemia treatment.
Calcitonin is safe and does not have major toxicities. The effect is fast despite the weakness. It starts in six hours and reduces calcium up to 1-2 mg / dL maximum. Probably due to receptor down-regulation, tachyphylaxis develops within 48 hours.

Bisphosphonates

Bisphosphonates are nonhidrolizable analogs of inorganic phosphate adsorbing to the surface of bone hydroxyapatite. It disrupts osteoclast-mediated bone resorption and impairs calcium release.
Although zoledronic acid has the potential to cause osteonecrosis of the jaw, it is a side effect that is more commonly seen in chronic use.
The efficacy of zolendronic acid 4 mg and 8 mg doses were similar. 8 mg was associated with more renal toxicity.
Pamidronate is more effective than etidronate or clodronate.
Ibandronate 2mg / 4mg / 6mg is also effective in hypercalcemia. The efficacy is greater at 4 mg and 6 mg, but duration of action is dose independent.
Ibandronate appears to be as effective as pamidronate.
Clodronate and etidronate are relatively low-impact first-generation bisphosphonates. If the other bisphosphonates are not aviable, these two agents can be used.

Glucocorticoids

Where absorption of vitamin D-related dietary calcium is increased, glucocorticoids reduce the production of calcitriol within 2-5 days.

Denosumab

DenoSumab has a 60 mg injector and is used weekly.
It can also be used in chronic kidney failure. Optimal dosing is not clear in renal failure. The risk of hypocalcemia seems to be more in chronic kidney disease.
If the first dose is as low as 0.3 mg / kg, and if the target is not reached within 1 week, the second injection may be recommended as a prudent approach, considering the risk of hypocalcemia.
Measuring vitamin D levels prior to denosumab may also be warranted, because those with vitamin D deficiency are more susceptible to hypocalcemia. Even if the measurement of vitamin D levels is delayed, give vitamin D 50000 IU 1-2 days before donesumab; If the result is Vitamin D deficiency you will continue treatment; If there are no deficiencies, you will end up giving vitamin D. Some authors advocate this view.

Calcimimetics

Sinekalset

Dialysis

It is the approach to be considered in the last stage.