Introduction (400-600 words):



538

Hepatitis C virus (HCV) was first identified in patients with transfusion-associated hepatitis in which Feinstone and team in 1975 found no relation to viral hepatitis type A or B and so classifying HCV as non-A, non-B hepatitis (Feinstone

et al.,

1975). HCV is a positive-sense single stranded RNA belonging to the Flaviviridae family and

Hepacivirus

genus (Chevaliez and Pawlotsky, 2008) and due to its RNA nature and the absence of proofreading activity (Tsukiyama-Kohara and Kohara, 2018), HCV can suffer genetic mutations which can evade the host immune response as well as antiviral medication during a viral infestation. This prolonged evasion may result in viral resistance leading to chronic hepatitis C (Thomson, Smith and Klenerman, 2011). Chronic hepatitis can also be caused due to infected people being unaware of the problem as HCV usually does not show any symptoms until the liver sustain a certain degree of damage (Volk

et al.,

2009).

According to WHO (World Health Organization), approximately 71 million people suffer from chronic hepatitis C infection, of which many of these cases will further develop into cirrhosis and hepatocellular carcinoma which can lead to death. Hepatitis C is responsible for nearly 400,000 deaths per year and to date there is no preventive vaccine (WHO, 2018).

Nowadays, HCV is classified into 7 different genotypes which further divided into 67 subtypes (Smith

et al.,

2014). The prevalence of different genotypes varies in different countries. The genotype 1 being the most common worldwide and predominant in Europe, North and Latin America. Genotype 3 is the next most recurrent worldwide, of which a good proportion is seen in south Asia. Genotype 2 and 6 are commonly seen in east Asia and genotype 4 is largely present in North Africa and Middle East. Genotype 5 accounts for the least common genotype of all and it is most commonly found in Southern and Eastern sub-Saharan Africa (Messina

et al.,

2015).

The diagnosis of HCV is done by detecting the presence of anti-HCV antibodies and HCV RNA load in the serum, which can be achieved by enzyme immunoassay for the first and molecular amplification for the second. Real-time reverse-transcriptase PCR is a reliable technique used for HCV RNA quantification and genotype detection nowadays (Chevaliez and Pawlotsky, 2008)

For many years the standard treatment given to patients was the combination of pegylated interferon and ribavirin, with and average success rate of 50% varying from genotype to genotype (Webster, Klenerman and Dusheiko, 2015), additionally it is an expensive and prolonged treatment which can cause adverse reactions, the usual timeframe of this treatment for genotype 1 and 4 is 48 weeks while genotypes 2 and 3 require half of that time(Halliday, Klenerman and Barnes, 2011). From 2014 onwards, a new generation of therapy called Direct Acting Antivirals (DAA) were developed with success rates above 90% including patients with chronic HCV (Pawlotsky, 2014).

For a treatment to be considered successful and the patient “cured”, the patient needs to achieve sustained virologic response (SVR) which is defined by the undetectable levels of the virus RNA 24 weeks after the end of treatment, furthermore, relapse after achieving SVR is less than 1% in patients with chronic HCV (Lindsay, 2002). Nonetheless, reinfection can occur, especially in ongoing injecting drug users (Grebely

et al.,

2012).

Results:



(600-1000 words) 946

The blood analysis of the patient in his first visit seen in table 1 revealed that the total bilirubin present in the blood was 3.9mg/dL indicating hyperbilirubinemia and explaining the patient’s jaundice; Liver enzyme ALT (Alanine transaminase) was 136 U/L and were also above the normal range which indicated liver damage; The presence of hepatitis C virus was positive, the titre for the anti HCV antibody was 1/80 dilution which shows the presence of antibodies against HCV in a higher dilution than the cut-off of 1/20 and the levels of HCV RNA in the bloodstream were 100,000 IU/ml, well above the cut-off limit of 200 IU/ml. Anti-Hepatitis A virus (anti-HAV) was negative for the presence of immunoglobulin M (IgM) antibody to HAV, and Hepatitis B surface antigen (HBsAg) was also negative, both results excluded the presence of Hepatitis A or B; Antinuclear antibody (ANA) was negative for the presence of autoantibody which means that there’s no evidence of an autoimmune disorder; Anti-mitochondrial antibody (AMA) were negative for the presence of autoantibodies against liver cells and thus excluding the presence of the autoimmune disease Primary Biliary Cirrhosis (PBC).

Table 1.

Lab investigations of the patient X at the time of his first visit to his physician.

Highlighted in red are the results well above the limit of normal range, which shows that the patient is positive for HCV and presented abnormal liver function. The negative results for anti-HAV and HBsAg rules out the presence of Hepatitis A or B; ANA and AMA results were negative for the presence of autoantibodies and primary biliary cirrhosis (PBC) respectively.

The HCV sample from the patient (isolate) were identified in the first screen by sequencing the hypervariable region of envelope E2 gene and analysed on nucleotide sequence BLAST search. The analysis in seen on table 2. The patient isolate had a 100% identity match with “Hepatitis C virus subtype 1a polyprotein gene, complete cds” (sequence ID: AF009606) and 99% identity match with the complete genome of Hepatitis C virus subtype 1a (sequence ID: M67463.1), both indicating that the patient’s HCV genotype was 1a.

First identity match:

Second identity match:

Table 2.

Sequence analysis of patient HCV isolate.

Patient HCV isolate have a high identity match with the genotype 1a. Highlighted in yellow is the percentage of identity match of each comparison.

The patient HCV load was recorded over a period of 42 weeks and presented in log10 with a linear graph (table 3). The results showed a substantial reduction of HCV RNA in the first 4 weeks of treatment starting from log

₁₀

(550,000) = 5.75 IU/ml on the first week down to log

₁₀

(15,000) = 4.18 IU/ml on week 4. The viral load kept reducing significantly until week 12, going from log

₁₀

(15,000) = 4.18 IU/ml on week 4 to log

₁₀

(980) = 2.99 IU/ml on week 6 down to log

₁₀

(110) = 2.04 IU/ml on week 12. From week 18 onwards the values were bellow the cut-off value of log

₁₀

(200) = 2 UI/ml and thus considered bellow the limit of the detection.

Table 3.

Effect of pegylated interferon and ribavirin on serum viral load in patient X (detection limit for HCV RNA is log



₁₀



(100) = 2 IU/ml)


.

The results seen on the linear graph are represented in Log10. The graph shows substantial reduction of the viral RNA from week 0 to 12; From week 18 onwards the virus is considered undetectable because it is below the cut-off limit.

The liver biopsy (fig. 1) done during the patient’s second visit to the hospital (2 years after the first diagnosis) shows significant necrosis of hepatocytes. There’s a great number of infiltrating lymphocytes, especially in the portal areas, causing inflammation – this is a characteristic of chronic hepatitis, and the presence of regenerative nodules that lost their normal architecture and high level of fibrotic tissue extending between portal tracts surrounding the regenerative nodules, these are the main characteristics of cirrhosis. Within the fibrotic tissue it is possible to see lymphocytes scattered all around along with proliferated bile ducts. The section also shows the presence of disorganised sinusoids which impairs the normal flow of the liver, swollen hepatocytes due to inflammation, few fat deposits, and no evidence of hepatocellular carcinoma.

Figure 1.

Histopathological section of the liver biopsy.

This trichrome stainedmicrograph shows abnormal shaped nodules surrounded by fibrotic tissue (greyish regions) with proliferation of bile ducts; great quantity of infiltrating lymphocytes seen all over the fibrous tissue and on the portal areas (blue circle). There’s also the presence of enlarged and disorganised sinusoids between the hepatocytes, little amount of fat deposits, and inflamed hepatocytes looking deformed and enlarged (orange circle).

During the second treatment given, the patient’s ALT and HCV RNA levels were checked for a period of 28 months – starting from month 36 after first diagnosis to month 64 – and the results are seen on table 4. On month 36 the levels of ALT were approximately 150 IU/L which was even higher than the first screen and well above the normal range of 7 to 56 units per litre. Throughout the following months the patient’s ALT levels remained above the normal range, reaching a minimum of approximately 125 IU/L 40 months after the initial diagnosis and a maximum of 160 IU/L on month 46. The patient’s HCV RNA load on month 36 was above 1,200,000 IU/ml (~ 6.1 Log

₁₀

IU/ml) which was 2x higher than the first diagnosis. Throughout the 28 months of the second treatment, the levels of viremia remained substantially high, with a minimum of ~316,000 IU/ml on month 64. This shows the lack of response to the pegylated interferon and ribavirin treatment given the second time around.

Table 4.

HCV RNA and ALT levels during a period of 28 months (second visit).

ALT normal range is 7 to 56 units per litre; HCV RNA cut-off is 1/20 dilution. The patient’s levels of ALT (blue) and HCV RNA (orange) remained substantially high during the second treatment and are indicatives of the non-response to the treatment given.

Throughout the patient’s first and second treatments his anti-HCV antibodies titre were analysed and are shown in a linear graph on table 5. The graph shows a steep increase on the first course of treatment, starting from 80 on the first month to 260 on month 9, indicating that the patient’s body was actively fighting the virus. However, even with the decreasing amount of HCV RNA seen on table 3, the anti HCV titre kept on rising. On his second visit to the hospital, the anti-HCV titre was 320, even higher than before and during his stay on the local hospital the titre showed a steadier increase going from 320 to 330 over a period of 28 months.

Table 5.

Anti-hepatitis C antibody titre in patient X.

During the firsttreatment (in blue) theanti HCV titre raised considerably from 80 to 260 in 9 months. On the second visit to the hospital (in green) the titre increased at a slower pace, going from 320 to 330 in 28 months with a small decline on month 48.

The HCV genotype was re-analysed by sequencing the hyper variable region 1 (HVR1) of the envelope E2 gene seen on table 5. Clone 1 isolate had a 100% match with “Hepatitis C virus 3a isolate Pk/173D envelope protein 2 gene, partial cds” (sequence ID:

HM584121.1

); Clone 2 had 100% identity match with isolate “Hepatitis C virus isolate PK/248E envelope protein E2 gene, partial cds” (sequence ID: HM590017.1), which is a variable isolate from the genotype 3a; Clone 3 had 100% identity match with isolate  “Hepatitis C virus 3a isolate PK/173b envelope protein 2 gene, partial cds” (sequence ID: HM584119.1). All clones indicated the presence of three closely related variants from the genotype 3a and had no identity match with the genotype 1a given in the first diagnosis.

Table 5.

Clones 1, 2 and 3 of the sequence data of the hyper variable region 1 of the envelope E2 gene from patient isolate (second screen).

All three clones from the second screen of the patient isolate had 100% identity match with the genotype 3a (highlighted in yellow). Clone 1 had a 100% match with isolate Pk/173D; Clone 2 had 100% match with isolate PK/248E; Clone 3 had a 100% match with isolate PK/173b.

Discussion: (500-700 words)




574

Upon evaluation of the history of patient’s drug addiction, initial symptoms of jaundice and first test results seen on table 1 combined with the biopsy of the liver (figure 1) done 2 years later in the local hospital showing cirrhosis, it is conclusive that the patient had been suffering from chronic hepatitis and cirrhosis since before the first visit to the hospital, considering that hepatitis C is most of the time asymptomatic and it can take a long time for the liver to obtain some degree of damage and cause visible symptoms such as jaundice (Zaltron

et al.,

2012) and an even longer time for progression to cirrhosis, which can take decades to occur (Seeff, 2002).

The patient initial genotype was 1a and it was recommended 48 weeks of pegylated interferon with ribavirin, of which he stopped at week 46. The patient’s viral load had a rapid decline and remained undetected for several weeks as seen on table 2, suggesting that the he was having a good response to the treatment given, however, there were no further checks of his HCV RNA load after week 42 and thus no evidence of when exactly the levels of viremia raised again.

On the second visit to the hospital the patient’s symptoms had worsened, he presented advanced jaundice which is explained by the severe liver damage seen on the liver biopsy, he also had signs of ascites and splenomegaly, the first resulting from portal hypertension, which is the resistance of the normal blood flow in the portal regions of the liver caused by cirrhosis (Christopher M Moore and David H Van Thiel, 2013), and the second is commonly seen in chronic infections and cirrhosis (Liang Li

et al.,

2017). The second analyses of the viral genotype returned with a new strain of HCV – genotype 3a – and no signs of the genotype 1a. This suggests that the patient may have been reinfected with the new strain, which is further supported by the patient’s history of drug addiction and the constant high levels of ALT (seen on table 4) which may be a good indicative of reinfection (Grebely

et al.,

2012).

The patient remained with high levels of viremia and ALT for over 2 years after the second failed treatment, which must have caused even further damage to the liver, aggravating the diagnosis. Due to the severity of the cirrhosis and the presence of ascites, a liver transplant should be considered, as ascites is an indicative of decompensated cirrhosis and it has poor prognosis with a mortality rate of 50% within 2 years (O’Neill and Oniscu, 2017), however, a liver transplant before treating the HCV infection could result in the recurrence of the disease and an even faster progression to cirrhosis (Forns

et al.,

2015). A new course of treatment should be given before liver transplantation, this time using DAA which directly targets the viral strain. Recent studies show successful cases of HCV genotype 3 patients achieving SVR even with decompensated cirrhosis by being prescribed a Sofosbuvir based treatment (Dalgard

et al.,

2017), in one case there were even an improvement in renal function which eliminated the need for liver transplant afterwards (Flemming and Lowe, 2016).

Based on the patient HCV infection and degree of liver damage it is conclusive that treatment of HCV should be done prior to a possible liver transplant, and even if there’s an improvement of liver function, close monitoring of such is required.

Furthermore, the patient should get help with the drug addiction, because if a transplant is required, he may be disqualified.

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The Impact of Maternal Depression and Anxiety on Fetal Development

Abstract

The purpose of this review paper is to briefly review past and present literature on the impact of maternal depression and anxiety during pregnancy to the developing fetus.  We will be reviewing the prenatal risks involved in untreated depression during pregnancy.  We will be looking at depression and anxiety during pregnancy as risk factors for adverse outcomes to both mothers and fetal development.  As well as depression and anxiety being an insult to both neurological and neurobehavioral development of fetuses exposed during pregnancy.

Keywords: Fetal Development, Depression, Anxiety, Pregnancy, Prenatal, Insult, Neurological, Neurobehavioral

Introduction

This paper will be reviewing the current and past research on maternal depression, anxiety and its impact on fetal development. (Schetter, Tanner, 2012)  We will be looking at the prevalence and associated factors of depression, and anxiety during pregnancy. (Nasreen, et. al., 2011)  Links between increased uterine artery resistance and maternal anxiety and depression during pregnancy.

(Teixeira, et. al., 1999)

Newborn neurobehavioral patterns related to prenatal major depressive disorder. (Kinsella, Monk., 2009)  Stillbirths and other outside variables that are risk factors for depression and anxiety in subsequent pregnancies. (Hughes, et. al., 1999)  The prenatal, perinatal and postnatal risks of untreated depression. (Bonari,et. al., 2004)

Antenatal maternal anxiety as related to HPA-axis dysregulation. (Bergh, et. al, 2007)

We will not be discussing medications, treatments or care plans outside of those that were mentioned in the study.

Discussion

Pregnancy can be one of the most wonderful and breathtaking experiences in a women’s life, a time of great fulfillment.  However, it can also be a time of great stress, worry and anxiety.  At any given moment there are roughly 12.4 births per 1,000 population in the Unites States alone.  Which in 2015 came to a total of 3,978,497 births for that year . (CDC, 2015)].  Suffices to say that this is an area of some importance and needs to be researched and explored in some depth.  Particularly the maternal state of wellbeing.  The World Health Organization (WHO) estimates that by 2020 depressive disorders will be the second leading cause in global disease burden.  Already it is the leading cause of death for 15-29-year-olds. (WHO, 2018).  It was not listed as to how many of those 15-29-year-olds are pregnant women, but it would be in interesting question for future research and one worth considering.

For some time, psychologists, psychiatrist and other related disciplines and experts have expressed concern about pregnant women experiencing the telltale signs of anxiety, depression and stress during pregnancy and in postpartum. (Schetter et. al., 2012).  This is especially true for vulnerable populations of women such as those that live in rural or impoverish conditions with little to no help or support.  A study done in rural Bangladesh showed a prevalence of antepartum depressive (ADS) 18% and anxiety symptoms (AAS) was 29% with a total ending N=671. [See figure 1. (Nasreen, et. al., 2011)].

Recent studies have shown that anxiety and depression in pregnancy have had adverse implications for embryonic and fetal development.  Ranging from the neurological/neurobehavioral (Salisbury, e.t al. 2011), to the physiological (Teixeira et. al., 1999), and well after birth. (Schetter, et. al., 2012)  A study done by Salisbury, et. al. found evidence that suggests  women with depression and infants’ exposure to maternal depression during pregnancy have higher levels of norepinephrine and cortisol metabolites with decreased dopamine compared to nondepressed pregnant women and their infants.  To drive the point further their research, suggest newborns prenatally exposed to maternal depression showed low muscle tone, irritability, reactivity and more difficulty with behavioral state regulation. [See figure 2 (Salisbury, e.t al. 2011)].

In most societies it is accepted that psychological states during pregnancy can influence the developing fetus. Some studies have showed infants of depressed and anxious mothers are born with a significantly lower weight and born earlier when compared with those whose mothers were not depressed.  One large study even showed that depression, stress, and anxiety had the same low birth weight effect as those who were born from mothers who smoked. (Teixeira, et. al., 1999).  Animal studies have shown that when the mother is stressed during pregnancy, birth weight is reduced, and behavior is permanently affected. (Teixeira, et. al., 1999).  Two mechanisms have been shown to stress or cause anxiety that potentially will affect the fetus. Increased hormone concentration from the mother that is then transported through the placenta to the fetus. And blood flow becoming impaired through the uterine arteries.  These arteries may develop a resistance to blood flow as demonstrated by the presence of notches in waveform patterns seen by using a color doppler. [See figure 3 (Teixeira, et. al., 1999)].  These notches are associated with abnormal blood flow and denotes a high resistance to blood flow.  This effect has been demonstrated in primates but has not been studied in humans. (Teixeira, et. al., 1999) This had previously been seen in cases of gestational diabetes and pre-eclampsia. (Kinsella, Monk, 2009)

Some inferentially projected estimates place the prevalence of depression during pregnancy as high as 16% with 5% of those women displaying symptoms of major depressive disorder. (Schetter, et. al., 2012).  That said, there is a small caveat, and some have pointed to this. Experts have questioned the ability to appropriately diagnoses the depressive disorders using standard diagnostic criteria.  This is because the symptoms of the criteria are typical symptoms of pregnancy such as sleep disturbance, appetite changes, and fatigue. (Schetter, et. al., 2012).  But even with that being taken into consideration there is still an overwhelming amount of supporting research on the negative impact for pregnant mothers and teratogenic effects on fetal development from maternal depression and anxiety (Nasreen, et. al., 2011).

A study done in 1999 by P. M. Hughes, P. Turton, and C. D. H. Evans which focused on factors for depression and anxiety in pregnant women.  Looked at factors preluding pregnancy, in this case stillbirths were the choice topic of study.  Still births are, as defined by the Oxford English Dictionary, “The birth of an infant that has died in the womb – strictly, after having survived though at least the first 28 weeks of pregnancy.” (Oxford Dictionary, 2018).  Stillbirths create a vulnerability to depression and anxiety in any following pregnancies. (Hughes, et. al., 1999).  With this we can deduce that women who have had stillbirths are starting off with a  predisposition for depression and anxiety for the next pregnancy.  Depression from the lost pregnancy and the anxiety of what could happen with the next pregnancy could create an unfavorable combustible mixture. In fact, in the afore mentioned study it was noted that conception within a year of a stillbirth is associated with higher levels of depression and anxiety in that pregnancy than compared to conceptions much later.  This suggests that new pregnancies interfere with the normal mourning process. [See figure 4. (Hughes, et. al., 1999)].

It is lamentable the treatment of maternal depression has not received the appropriate level of attention: outside of medical studies in which they have attempted to determine potential but unproven risks of antidepressants. (Bonari, et. al., 2004).  Lifetime depression  risks from community-derived samples have estimated between 10%-25% of pregnant women will develop depression. (Bonari, et. al., 2004).  In one study 20% of obstetrics patients were randomly screened met the diagnosable criteria for depression. (Bonari, et. al., 2004).  With depression having such prevalence some researchers have suggested and believe pregnancy to be a risk factor for mood disorder to those who have a history of mood disorders. (Bonari, et. al., 2004).  In a study done by (Marcus et. al.,2003), they found 1 in 5 pregnant women experience depression during their pregnancy, but few seek treatment.  This study had an N=3,472 and showed both an undertreatment and underdiagnosis of depression.  Of those, 20% were found to have scored high on the Centre for Epidemiological Studies Depression Scale or CESD for short.  While this is not technically a clinical diagnosis only 13.8% of these pregnant women were receiving and kind of care.  The 86.2% remaining women were not receiving any form of treatment. [See figures 5,6,7 for summary depression studies, (Marcus et. al.,2003)].  The conclusion of the study stated that stigma attached with having depression during pregnancy has and may continue to prevent women from seeking help or reaching out to family and friends.  A pregnant woman might feel guilty for doing so because pregnancy is supposed to be a time of happiness and joy. (Bonari, et. al., 2004).

This has devastating consequences for fetal development as depression has been associated with hypothalamo-pituitary-adrenal (HPA) axis hyperactivity. (Bonari, et. al., 2004).  Peptides from the activated HPA axis regulate maternal stress, anxiety and depression and are thought to affect birth outcomes as well.  It may even, in crossing into the placenta, directly affect fetal growth.  So, not only does maternal depression activate the mothers HPA axis, it may induce an increase in the release of corticotropin-releasing hormone (CRH) from the placenta through catecholamines and cortisol. (Bonari, et. al., 2004).  The timing of delivery may also be affected by the CRH which would explain why women with depression show higher rates of premature labor verses those women who do not have depression. (Bonari, et. al., 2004).  Recent research with animals in this field have found that the stress during pregnancy is associated with dysfunctions of the HPA axis and fetal tissue development. (Bonari, et. al., 2004).  Another hypothesis put forth is that the depression alters excretion of the vasoactive hormones and neuroendocrine transmitters, which then induce the vascular changes we see in pregnant women.  (Bonari, et. al., 2004).  We can see a picture begin to develop here of the risks for both the women and fetal development in untreated depression during pregnancy.

Conclusion

In conclusion we can see that maternal depression and anxiety during pregnancy is a field of research just getting started.  As we learn more about the brain, we are sure to discover more about this.  We have looked at and considered current and past research on maternal depression and anxiety and its impact of fetal development. (Schetter, Tanner, 2012).  But there is still more to be done. We would be doing a disservice to the millions of pregnant women around the world by not conducting more studies, more research and providing more assistance for them. Maternal depression and anxiety on fetal neurobehavioral development should become a larger focus as we begin to understand  and learn more about embryonic development. (Salisbury, et. al., 2011).  We have reviewed the biological impacts and teratogenic affects. (Teixeira, et. al., 1999).  We have looked at external contributing variables such as stillbirths that are risk factors for depression and anxiety in subsequent pregnancies. (Hughes, et. al., 1999).  We have reviewed the risks of untreated depression during pregnancy (Bonari, et. al., 2004).  And we have ended with antenatal maternal anxiety as related to HPA-axis dysregulation. (Bergh, et. al, 2007).

References

1. Bergh, Bea RH, V., Calster, Ben, V., Smits, Tim, et. al. (2007).  Antenatal Maternal Anxiety Is Related To HPA-Axis Dysregulation And Self-Reported Depressive Symptoms In Adolescence: A Prospective Study On The Fetal Origins Of Depressed Mood, Neuropsychopharmacology (2008) 33, 536-545
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